(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
1 August 2002 (01.08.2002)
PCT
(10) International Publication Number
WO 02/058696 A2
(51) International Patent Classification 7 : A61K 31/397,
A6 IP 3/06, 9/10
(21) International Application Number: PCT/US02/01 195
(22) International Filing Date: 25 Jan uary 2002 (25. 01.2002)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
607264,645 26 January 2001 (26.01.2001 ) US
(71) Applicant: SCHER1NG CORPORATION [US/US];
Patent Department - K-6-1 1990, 2000 Galloping Hill
= Road. Kenilworth. NJ 07033-0530 (US).
(72) Inventor: DAVIS, Harry, R.; 64 River Bend Road, Berke-
|H ley Heights, NJ 07922 (US).
HI (74) Agent: CANNONI, Ann, Marie; Patent Department
IHH K-6-l, 2000 Galloping Hill Road. Kenilworth, NJ
07033-0530 (US).
(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA. CH. CN. CO, CR. CZ,
DE, DK, DM, DZ, EC, EE, ES, R, GB, GD, GE, HR, HII,
ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LU, LV,
MA, MD, MG, MK. MM, MX, MZ, NO, NZ, PH, PL, PT,
RO, RU, SE, SG, SI, SK, SL. TJ, TM, TN, TR, TT, TZ, UA,
UZ, VN, YU, ZA, ZM.
(&4) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ. UG, ZM, ZW),
Eurasian patent (AM. AZ, BY, KG, KZ, MD, RU, TJ, TM ),
European patent (AT, BE, CH, CY. DE, DK, ES, FI, FR,
GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAP! patent
(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
NE, SN, TD, TG).
Declaration under Rule 4.17:
— as to the applicant s entitlement to claim the priority of the
earlier application (Rule 4.17(iii)) for all designations
Published:
— without international search report and to be republished
upon receipt of that report
For two-letter codes and oilier abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
<rN|
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(nn
® (54) Title: THE USE OF SUBSTITUTED AZETIDFNONE COMPOUNDS FOR THE TREATMENT OF S1TOSTEROLEMI A
<N1
(57) Abstract: The present invention is directed to the use of sterol absorption inhibiting compounds, pharmaceutical compositions
Q thereof, therapeutic combinations and their use in combination with other lipid lowering agents to treat or prevent sitosierolcmia
^ and/or to lower the concentration of sierol(s) other than cholesterol in plasma or tissue of a mammal. Methods of treating or prevent-
ed ing vascular disease nnd coronary events also are provided.
1 "1
THIS PAGE BLANK »*n<»
WO 02/058696 PCT/US02/0 1 1 95
THE USE OF SUBSTITUTED AZETIDINONE COMPOUNDS FOR THE
TREATMENT OF SITOSTEROLEM1A
CROSS-REFERENCE TO RELATED APPLICATION
5 This application claims the benefit of U.S. Provisional Application
Serial No. 60/264,645 filed January 26, 2001.
FIELD OF THE INVENTION
The present invention provides methods and pharmaceutical compositions
10 for treating or preventing sitosterolemia by administering to a mammal in need of
such treatment an effective amount of at least one treatment composition
comprising at least one sterol absorption inhibitor and optionally, an effective
amount of at least one bile acid sequestrant or other lipid lowering agent.
15 BACKGROUND OF THE INVENTION
Sitosterolemia is a genetic lipid storage disorder characterized by increased
levels of sitosterol and other plant sterols in the plasma and other tissues due to
increased non-selective intestinal absorption of sterols and decreased hepatic
removal. Individuals having sitosterolemia can exhibit one or more of the following
20 conditions: tendon and tuberous xanthomas, arthritis, hemolytic episodes,
accelerated atherosclerosis and myocardial infarctions, and can die at an early age
due to extensive coronary atherosclerosis. See Nguyen et al., "Regulation of
cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and
dietary sterol restriction", Vol 32, Journal of Lipid Research , pp. 1941-1948, (1991),
25 incorporated by reference herein.
Sitosterolemia can be treated with bile acid sequestrants (such as
cholestyramine, colesevelam hydrochloride and colestipol), however, these
compounds have a tendency to cause constipation in patients and therefore
compliance with this treatment is difficult. Bile acid sequestrants (insoluble anion
30 exchange resins) bind bile acids in the intestine, interrupting the enterohepatic
circulation of bile acids and causing an increase in the fecal excretion of steroids.
Use of bile acid sequestrants is desirable because of their non-systemic mode of
action. Bile acid sequestrants can lower intrahepatic cholesterol and promote the
WO 02/058696 PCT/US02/01 195
2
synthesis of apo B/E (LDL) receptors which bind LDL from plasma to further reduce
cholesterol levels in the blood.
Alternative treatments include ileal bypass surgery and selective low density
lipoprotein plasmapheresis, which are physically undesirable for the patient.
An improved treatment for sitosterolemia is needed which can reduce the
concentration of sterols in plasma and tissues and inhibit associated debilitating
physical effects. Also, treatments which reduce the plasma or tissue concentration
of non-cholesterol sterols such as phytosterols and 5a-stanols are needed.
SUMMARY OF THE INVENTION
The present invention provides a method of treating or preventing
sitosterolemia, comprising administering to a mammal in need of such treatment an
effective amount of at least one sterol absorption inhibitor, or pharmaceutically
acceptable salt or solvate of the least one sterol absorption inhibitor, or prodrug of
the at least one sterol absorption inhibitor or pharmaceutically acceptable salt or
solvate of the least one sterol absorption inhibitor, or mixture thereof.
In another embodiment, the present invention provides a method of treating
or preventing sitosterolemia, comprising administering to a mammal in need of
such treatment: (1) an effective amount of at least one sterol absorption inhibitor, or
pharmaceutically acceptable salt or solvate of the least one sterol absorption
inhibitor, or prodrug of the least one sterol absorption inhibitor or pharmaceutically
acceptable salt or solvate of the least one sterol absorption, or mixture thereof; and
(2) an effective amount of at least one bile acid sequestrant or other lipid lowering
agent.
In another embodiment, the present invention provides a method of treating
or preventing sitosterolemia comprising administering to a mammal in need of such
treatment: (1 ) an effective amount of at least one sterol absorption inhibitor, or
pharmaceutically acceptable salt or solvate of the least one sterol absorption
inhibitor, or prodrug of the least one sterol absorption or pharmaceutically
acceptable salt or solvate of the least one sterol absorption inhibitor, or mixture
thereof; and (2) at least one sterol biosynthesis inhibitor.
Other embodiments of the present invention include pharmaceutical
compositions for the treatment or prevention of sitosterolemia comprising an
WO 02/058696 PCT/US02/01 195
3
effective amount of the compositions or combinations used in the methods
described above in a pharmaceutically acceptable carrier.
Another embodiment of the present invention is a method of reducing
plasma or tissue concentration of at least one non-cholesterol sterol (such as a
phytosterol), 5a-stanol, or mixture thereof, comprising administering to a mammal
in need of such treatment an effective amount of at least one treatment composition
comprising an effective amount of at least one sterol absorption inhibitor or at least
one stanol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the
least one sterol absorption inhibitor or the at least one stanol absorption inhibitor, or
prodrug of the least one sterol absorption inhibitor or the at least one stanol
absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one
sterol absorption inhibitor or the at least one stanol absorption inhibitor, or mixture
thereof.
Yet another embodiment of the present invention is a method of reducing
plasma or tissue concentration of at least one non-cholesterol sterol, 5a-stanol f or
mixture thereof, comprising administering to a sitosterolemic mammal in need of
such treatment an effective amount of at least one treatment composition
comprising an effective amount of at least one sterol absorption inhibitor or at least
one stanol absorption inhibitor, or pharmaceutically acceptable salt or solvate of the
least one sterol absorption inhibitor or the at least one stanol absorption inhibitor, or
prodrug of the least one sterol absorption inhibitor or the at least one stanol
absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one
sterol absorption inhibitor or the at least one stanol absorption inhibitor, or mixture
thereof.
In another embodiment, the present invention provides a method of treating
vascular disease, arteriosclerosis and/or atherosclerosis, comprising administering
to a mammal in need of such treatment an effective amount of at least one
treatment composition comprising an effective amount of at least one sterol
absorption inhibitor or at least one stanol absorption inhibitor, or pharmaceutically
acceptable salt or solvate of the least one sterol absorption inhibitor or the at least
one stanol absorption inhibitor, or prodrug of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor or pharmaceutically
acceptable salt or solvate of the least one sterol absorption inhibitor or the at least
WO 02/058696 PCT/US02/0 1 1 95*
4
one stanol absorption inhibitor, or mixture thereof to reduce plasma or tissue
concentration of at least one non-cholesterol sterol, 5a-stanol or mixture thereof.
In another embodiment, the present invention provides a method of
preventing or reducing risk of a cardiovascular event comprising administering to a
mammal an effective amount of at least one treatment composition comprising an
effective amount of at least one sterol absorption inhibitor or at least one stanol
absorption inhibitor, or pharmaceutical^ acceptable salt or solvate of the least one
sterol absorption inhibitor or the at least one stanol absorption inhibitor, or prodrug
of the least one sterol absorption inhibitor or the at least one stanol absorption
inhibitor or pharmaceutical^ acceptable salt or solvate of the least one sterol
absorption inhibitor or the at least one stanol absorption inhibitor, or mixture thereof
to reduce plasma or tissue concentration of at least one non-cholesterol sterol, 5a-
stanol or mixture thereof.
In another embodiment, the present invention provides a method of
preventing or reducing risk of a cardiovascular event comprising administering an
effective amount of at least one treatment composition as described above to
reduce plasma or tissue concentration of at least one non-cholesterol sterol, 5a-
stanol or mixture thereof to a mammal having no history of clinically evident
coronary heart disease prior to the initial administration.
Other than in the operating examples, or where otherwise indicated, all
numbers expressing quantities of ingredients, reaction conditions, and so forth
used in the specification and claims are to be understood as being modified in all
instances by the term "about."
DETAILED DESCRIPTION
The present invention provides methods, pharmaceutical compositions and
combinations for treating or preventing sitosterolemia and conditions or symptoms
associated with sitosterolemia such as are discussed above. Another aspect of the
present invention provides methods, pharmaceutical compositions and
combinations for reducing the plasma or tissue concentration of non-cholesterol
sterols, such as phytosterol(s), and/or 5a-stanol(s). or mixtures thereof, in a
mammal which can be useful in the treatment and/or prevention of vascular
conditions or disease, such as vascular inflammation, arteriosclerosis,
WO 02/058696 PCT/US02/01 195
5
atherosclerosis, hypercholesterolemia and sitosterolemia, and cardiovascular
events, stroke and/or obesity.
Useful treatment compositions comprise one or more sterol absorption
inhibitors and/or stanol absorption inhibitors such as are represented by Formulae
(l-XI) shown below.
In one embodiment one or more sterol absorption inhibitors and/or stanol
absorption inhibitors useful in the methods, compositions or combinations of this
invention are represented by Formula (I):
R 1
Ar 1 -A-Y-C-Z p v Ar 3
R 2
-N
0' W (I)
io or isomers of the compounds of Formula (I), or pharmaceutical^ acceptable salts
or solvates of the compounds of Formula (I) or of the isomers of the compounds of
Formula (I), or prodrugs of the compounds of Formula (I) or of the isomers, salts or
solvates of the compounds of Formula (I),
wherein in Formula (I):
is Ar 1 is R 3 -substituted aryl;
Ar 2 is R 4 -substituted aryl;
Ar 3 is R 5 -substituted aryl;
Y and Z are independently selected from the group consisting of -CH 2 -,
-CH(lower alkyl)- and -C(dilower alkyl)-;
20 A is -0-, -S-. -S(O)- or -S(0) 2 -;
R 1 is selected from the group consisting of -OR 6 , -0(CO)R 6 , -0(CO)OR9
and -0(CO)NR 6 R 7 ; R 2 is selected from the group consisting of hydrogen, lower
alkyl and aryl; or R 1 and R 2 together are =0;
q is 1, 2 or 3;
25 pis 0,1, 2, 3 or 4;
R 5 is 1-3 substituents independently selected from the group consisting of
-OR6 -O(C0)R6 -0(CO)OR9 -0(CH 2 ) v5 OR9 -0(CO)NR6r7, -NR6r7,
-NR6(CO)R 7 , -NR6(CO)OR 9 , -NR6(CO)NR7R8 f -NR6SQ 2 -lower alkyl,
WO 02/058696 PCT/US02/01 ^
6
-NR6S0 2 -aryl, -CONR6r7, . CO r6, -S0 2 NR6r7, S(OX«-alkyl. SfO^-aryl,
-O(CH 2 ) M0 -COOR6, -O(CH2) 1 . 10 CONR6r7, o-halogeno, m-halogeno, o-lower
alkyl, m-lower alkyl, -(lower alkylene)-COOR6, and -CH=CH-COOR 6 ;
R 3 and R 4 are independently 1-3 substituents independently selected from
the group consisting of R5, hydrogen, p-lower alkyl, aryl, -N0 2 , -CF 3 and
p-halogeno;
R 6 , R 7 and R 3 are independently selected from the group consisting of
hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R9 is lower alkyl,
aryl or aryl-substituted lower alkyl.
Preferred compounds of Formula I include those in which Ar 1 is R 3 -
substituted phenyl, especially (4-R 3 )-substituted phenyl. Ar 2 is preferably R 4 -
substituted phenyl, especially (4-R4)-substituted phenyl. Ar 3 is preferably R5-
substituted phenyl, especially (4-R5)-substituted phenyl. Mono-substitution of each
of Ar 1 , Ar 2 and Ar 3 is preferred.
Y and Z are each preferably -CH 2 -. R 2 is preferably hydrogen. R1 is
preferably -OR6 wherein R6 is hydrogen, or a group readily metabolizable to a
hydroxyl (such as -0(CO)R6, -0(CO)OR9 and -0(CO)NR6r7, defined above).
Also preferred are compounds wherein R 1 and R 2 together are =0.
The sum of q and p is preferably 1 or 2, more preferably 1. Preferred are
compounds wherein p is zero and q is 1. More preferred are compounds wherein p
is zero, q is 1 , Y is -CH 2 - and R1 is -OR6, especially when R6 is hydrogen.
Another group of preferred compounds is that in which Ar 1 is R 3 -substituted
phenyl, Ar 2 is R 4 -substituted phenyl and Ar 3 is R^-substituted phenyl.
Also preferred are compounds wherein Ar 1 is R 3 -substituted phenyl, Ar 2 is
R 4 -substituted phenyl, Ar 3 is R^-substituted phenyl, and the sum of p and q is 1 or
2, especially 1. More preferred are compounds wherein Ar 1 is R 3 -substituted
phenyl, Ar 2 is R 4 -substituted phenyl, Ar 3 is R^-substituted phenyl, p is zero and q
is 1.
A is preferably -0-.
WO 02/058696
PCT/US02/01195
7
R3 is preferably -COOR 6 , -CONR 6 R 7 -COR 6 -S0 2 NR 6 R 7 S(O) 0 . 2 -alkyl,
SfOJ^-aryl, N0 2 or halogeno. A more preferred definition for R3 is halogeno,
especially fluoro or chloro.
R 4 is preferably hydrogen, lower alkyl, -OR 6 , -0(CO)R 6 -0(CO)OR 9 ,
-0(CO)NR 6 R 7 , -NR 6 R 7 , COR 6 or halogeno, wherein R 6 and R 7 are preferably
independently hydrogen or lower alkyl, and R 9 is preferably lower alkyl. A more
preferred definition for R 4 is hydrogen or halogeno, especially fluoro or chloro.
R5 is preferably -OR 6 , -0(CO)R 6 , -0(CO)OR 9 -0(CO)NR 6 R 7 -NR 6 R 7 ,
-(lower alkylene)-COOR 6 or -CH=CH-COOR 6 , wherein R 6 and R 7 are preferably
independently hydrogen or lower alkyl, and R 9 is preferably lower alkyl. A more
preferred definition for R 5 is -OR 6 , -(lower alkylene}-COOR 6 or -CH=CH-COOR 6
wherein R 6 is preferably hydrogen or lower alkyl.
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formula (II):
or isomers of the compounds of Formula (II), or pharmaceutical^ acceptable salts
or solvates of the compounds of Formula (II) or of the isomers of the compounds of
Formula (II), or prodrugs of the compounds of Formula (II) or of the isomers, salts
or solvates of the compounds of Formula (II),
wherein in Formula (II) above:
A is selected from the group consisting of R 2 -substituted heterocycloalkyl,
R 2 -substituted heteroaryl, R 2 -substituted benzofused heterocycloalkyl, and
R 2 -substituted benzofused heteroaryl;
Ar1 is aryl or R^-substituted aryl;
Ar 2 is aryl or R 4 -substituted aryl;
19
0
(II)
WO 02/058696 PCT7US02/01 195
8
Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the
"Rf-(R 6 )a
/ R 7J |
spiro group v ,b ; and
R 1 is selected from the group consisting of:
-(CH 2 ) q -, wherein q is 2-6, provided that when Q forms a spiro ring, q can
5 also be zero or 1 ;
-(CH 2 ) e -G-(CH 2 ) r -, wherein G is -0-, -C(O)-, phenylene, -NR8- or
-SfO)^-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C 2 -C 6 alkenylene)-; and
-(CH 2 ) r V-(CH 2 ) g -, wherein V is C 3 -C 6 cycloalkylene, f is 1-5 and g is 0-5,
io provided that the sum of f and g is 1 -6;
R 5 is
ii ii i | I
-CH-, -C(C r C 6 alkyl)-, -CF-, -C(OH)-, -C(C 6 H 4 -R 9 )-, -N-. or- + NO" ;
R 6 and R 7 are independently selected from the group consisting of -CH 2 -,
-ChKCVCg alkyl)-, -C(di-(CVC 6 ) alkyl), -CH=CH- and -C^-Ce alkyl)=CH-; or R5
15 together with an adjacent R 6 , or R 5 together with an adjacent R 7 , form a -CH=CH-
or a -CH=C(C r C 6 alkyl)- group;
a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided
that when R 6 is -CH=CH- or -C(C r C 6 alkyI)=CH-, a is 1 ; provided that when R 7 is
-CH=CH- or -C{0 A -C 6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R 6 's
20 can be the same or different; and provided that when b is 2 or 3, the R 7 's can be
the same or different;
and when Q is a bond, R 1 also can be:
R 10 R 12 R 10 R 10
-M-Yd-C-Zh-.-X^CQs-Yn-CCh-Zp- or -X r (C) v -Y k -S(0)o. 2 -;
R 11 R 13 ^ R 11
M is -0-, -S-, -S(O)- or -S(0) 2 -;
25 X, Y and Z are independently selected from the group consisting of -CH 2 -,
WO 02/058696
PCT/US02/01195
9
-CH(C r C 6 alkyl)- and -C(di-(C r C 6 ) alkyl);
R 1 0 and R 12 are independently selected from the group consisting of
-OR 14 , -0(CO)R 14 -0(CO)OR 1 6 and -0(CO)NR 14 R 1 5 ;
R 1 1 and R 13 are independently selected from the group consisting of
hydrogen, (C r C 6 )alkyl and aryl; or R 10 and R 1 1 together are =0, or R 12 and R 13
together are =0;
d is 1 , 2 or 3;
h is 0, 1,2, 3 or 4;
s is 0 or 1; t is 0 or 1; m, n and p are independently 0-4; provided that at
least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when
p is 0 and t is 1, the sum of m, s and n is 1-5; and provided that when p is 0 and s
is 1 , the sum of m, t and n is 1 -5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
R 2 is 1-3 substituents on the ring carbon atoms selected from the group
consisting of hydrogen, (C^C^Jalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl,
(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkenyl, R 1 ^substituted aryl, R 17 -substituted
benzyl, R 17 -substituted benzyloxy, R 1 ^substituted aryloxy, halogeno, -NR 14 R 15 ,
NR 14 R 15(c r C 6 alkylene)-, NRl 4 Rl5c(0)(C r C 6 alkylene)-, -NHC(0)R 1 6 OH,
C r C 6 alkoxy, -0C(0)R16 -C0R1 4 , hydroxy(C 1 -C 6 )alkyl, (C r C 6 )alkoxy(C r C 5 )alkyl,
N02, -S(OV 2 R 1 6 -S0 2 NR1 4 R15 and -(C r C 6 alkylene)COOR 14 ; when R 2 is a
| (CU 2 h-2
substituent on a heterocycloalkyl ring, R 2 is as defined, or is =0 or O 7 ;
and, where R 2 is a substituent on a substitutable ring nitrogen, it is hydrogen,
(C r C 6 )alkyl, aryl, (C r C 6 )alkoxy f aryloxy, (C r C 6 )alkylcarbonyl, arylcarbonyl,
hydroxy, -(CH^CONR^rIS
wherein J is -0-, -NH-, -NR 13 - or -CH 2 -;
WO 02/058696 PCT/US02/01 195
10
R3 and R 4 are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of (C r C 6 )alkyl,
-OR 14 , -0(CO)R 14 , -0(CO)ORl6 t -OfCH^ORl 4 , -0(C0)NR1 4 R 15 , -NR1 4 R15
-NR1 4 (C0)R 15 , -NR 14 (C0)0R16, -NR1 4 (CO)NR15r19, -NR1 4 S0 2 R 1 6
-COOR1 4 , -CONRl 4 Rl5 t -COR1 4 , -S0 2 NR1 4 R15 S(0) M R16,
-O(CH 2 V 10 -COOR 14 -O(CH 2 ) 1 . 10 CONR1 4 r15 i .(C r C 6 alkylene)-COORl 4
-CH=CH-COOR 14 , -CF 3 , -CN, -N0 2 and halogen;
R8 is hydrogen, (C r C 6 )alkyl, aryl (C r C 6 )alkyl, -C(0)R1 4 or -COOR1 4 ;
R 9 and R 1 ? are independently 1-3 groups independently selected from the
group consisting of hydrogen, (C r C 6 )alkyl, (C r C 6 )alkoxy, -COOH, NO2,
-NRl 4 Rl5 f OH and halogeno;
R 14 and R 15 are independently selected from the group consisting of
hydrogen, (C r C 6 )alkyI, aryl and aryl-substituted (C r C 6 )alkyl;
R 16 is (C^C^alkyl, aryl or R 17 -substituted aryl;
R 18 is hydrogen or (C r C 6 )aIkyl; and
R 19 is hydrogen, hydroxy or (C r C 6 )alkoxy.
As used in Formula (II) above, W A M is preferably an R 2 -substituted, 6-
membered heterocycloalkyl ring containing 1 or 2 nitrogen atoms. Preferred
heterocycloalkyl rings are piperidinyl, piperazinyl and morpholinyl groups. The ring
n A" is preferably joined to the phenyl ring through a ring nitrogen. Preferred R 2
substituents are hydrogen and lower alkyl. R^ 9 is preferably hydrogen.
Ar 2 is preferably phenyl or R 4 -phenyl, especially (4-R 4 )-substituted phenyl.
Preferred definitions of R 4 are lower alkoxy, especially methoxy, and halogeno,
especially fluoro.
Ar 1 is preferably phenyl or R 3 -substituted phenyl, especially (4-R 3 )-
substituted phenyl.
There are several preferred definitions for the -R 1 -Q- combination of
variables:
Q is a bond and R 1 is lower alkylene, preferably propylene;
WO 02/058696 PCT/US02/01 195
11
Q is a spiro group as defined above, wherein preferably R 6 and R 7 are each
I i
ethylene and R 5 is -CH- or -C(OH)- ;
R 10
Q is a bond and R1 is -M-Y d -C-4- wherein the variables
R 11
are chosen such that R 1 is -0-CH 2 -CH(OH)-;
R 12 RIO
Q is a bond and R1 is -x m -(C) s -Y n -(C) t - Zp- wnerein tne
R 13 RH
variables are chosen such that R 1 is -CH(OH>-(CH 2 ) 2 -; and
R 10
Q is a bond and R1 is -X f (C) v -Y k -S(O) 0 . 2 - wherein the
R 11
variables are chosen such that R 1 is -CH(OH)-CH 2 -S(O) 0 . 2 -.
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formula (III):
R
ArV JC)^ S(0) r ^^ Ar2
Xm r 1 Yn Q
O "Ar 3
(III)
or isomers of the compounds of Formula (III), or pharmaceutically acceptable salts
or solvates of the compounds of Formula (III) or of the isomers of the compounds of
Formula (III), or prodrugs of the compounds of Formula (III) or of the isomers, salts
or solvates of the compounds of Formula (III),
wherein in Formula (III) above:
Ar 1 is aryl, R 10 -substituted aryl or heteroaryl;
Ar 2 is aryl or R 4 -substituted aryl;
Ar3 is aryl or R^-substituted aryl;
X and Y are independently selected from the group consisting of -CH 2 -,
WO 02/058696 PCT/US02/01 195
12
-CH(lower alkyl)- and -C(dilower alkyl)-;
R is -OR6, -0(C0)R6, -0(C0)0R9 or -0(CO)NR6r7 ; r1 j s hydrogen, lower
alkyl or aryl; or R and R 1 together are =0;
qisOoM;
r is 0, 1 or 2;
m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n
and q is 1, 2, 3, 4 or 5;
R 4 is 1-5 substituents independently selected from the group consisting of
lower alkyl, -OR6, -0(CO)R6, -0(CO)OR9, -OfCH^ORe, -0(CO)NR6r7, .
NR6R7, -NRe^OJR 7 , -NR6(CO)OR9, -NR6(CO)NR7r8, -NR6s0 2 R9, -COOR6
-CONR6R7, -COR6, -S0 2 NR6r7, S(0)o. 2 r9 -OfCI-y^-COORe,
-O(CH 2 ) 1 . 10 CONR6r7 > .(lower alkylene)COOR 6 and -CH=CH-COOR6;
R 5 is 1-5 substituents independently selected from the group consisting of
-OR6 -0(CO)R6, -0(CO)OR9, -0(CH 2 )^OR6 t -0(CO)NR6r7, -NR6R7,
-NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7r8, -NR6S0 2 R9, -COOR6,
-CONR6R7, -COR6, -S0 2 NR6r7, S(0)o. 2 R9, -O(CH 2 ) m0 -COOR6, 0{CH 2 ),.
10 CONR6r7, -cf 3 . -CN, -N0 2 , halogen, -(lower alkylene)COOR 6 and -CH=CH-
COOR6;
R 6 , R 7 and R 8 are independently selected from the group consisting of
hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R 9 is lower alkyl. aryl or aryl-substituted lower alkyl; and
R 10 is 1-5 substituents independently selected from the group consisting of
lower alkyl, -OR6 -0(00^6, -0(CO)OR9, -0(CH 2 ) 1 . 5 OR6 l -0(CO)NR6r7 j
-NR6r7, -NR6(CO)R7, -NR6(C0)0R9, -NR6(CO)NR7r8 -NR6s0 2 R9, -COOR 6 ,
-CONR6R7, -COR6, -S0 2 NR6r7, S(O) 0 . 2 R9, -0(CH 2 ) wo -COOR6,
-O(CH 2 ) 1 . 10 CONR6r7 > .cf 3 , -CN, -N0 2 and halogen.
Within the scope of Formula III, there are two preferred structures. In
Formula II IA. q is zero and the remaining variables are as defined above, and in
Formula II IB, q is 1 and the remaining variables are as defined above:
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PCT/US02/01195
R
TEA HIB
R 4 , R 5 and R 10 are each preferably 1-3 independently selected substituents
as set forth above. Preferred are compounds of Formula (III) wherein Ar 1 is
phenyl, R 10 -substituted phenyl or thienyl, especially (4-R 10 )-substituted phenyl or
thienyl. Ar 2 is preferably R 4 -substituted phenyl, especially (4-R 4 )-substituted
phenyl. Ar 3 is preferably phenyl or R 5 -substituted phenyl, especially (4-R 5 )-
substituted phenyl. When Ar 1 is R 10 -substituted phenyl, R 10 is preferably
halogeno, especially fluoro. When Ar 2 is R 4 -substituted phenyl, R 4 is preferably
-OR 6 , especially wherein R 6 is hydrogen or lower alkyl. When Ar 3 is
R 5 -substituted phenyl, R 5 is preferably halogeno, especially fluoro. Especially
preferred are compounds of Formula III wherein Ar 1 is phenyl, 4-fluorophenyl or
thienyl, Ar 2 is 4-(alkoxy or hydroxy)phenyl, and Ar 3 is phenyl or 4-fluorophenyI.
X and Y are each preferably -CH 2 -. The sum of m, n and q is preferably 2, 3
or 4, more preferably 2. When q is 1, n is preferably 1 to 5.
Preferences for X, Y, Ar 1 , Ar 2 and Ar 3 are the same in each of Formulae
MIA and HIB.
In compounds of Formula 111 A, the sum of m and n is preferably 2, 3 or 4,
more preferably 2. Also preferred are compounds wherein the sum of m and n is 2,
and r is 0 or 1 .
In compounds of Formula IIIB, the sum of m and n is preferably 1 , 2 or 3,
more preferably 1 . Especially preferred are compounds wherein m is zero and n is
1 . R 1 is preferably hydrogen and R is preferably -OR 6 wherein R 6 is hydrogen, or
a group readily metabolizable to a hydroxyl (such as -0(CO)R 6 -0(CO)OR 9 and
-0(CO)NR 6 R 7 , defined above), or R and R 1 together form a =0 group.
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formula (IV):
WO 02/058696 PCT/US02/01 195
14
(Rs)u-
O R 21
(IV)
or isomers of the compounds of Formula (IV), or pharmaceutically acceptable salts
or solvates of the compounds of Formula (IV) or of the isomers of the compounds
of Formula (IV), or prodrugs of the compounds of Formula (IV) or of the isomers,
salts or solvates of the compounds of Formula (IV),
wherein in Formula (IV) above:
R1 is
• I ii i i
-CH-, -Cflower alkyl)-, -CF-, -C(OH)-, -C(C 6 H 5 )-, -C(C 6 H 4 -R 15 )-,
i i
- N- or -N O" ;
i
R2 and R3 are independently selected from the group consisting of:
-CH 2 -, -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or
R1 together with an adjacent R2, or R1 together with an adjacent R3, form a -
CH=CH- or a -CH=C(lower alkyl)- group;
u and v are independently 0, 1 , 2 or 3, provided both are not zero;
provided that when R2 is -CH=CH- or -C(lower alkyl)=CH-. v is 1 ;
provided that when R3 is -CH=CH- or -C(lower alkyl)=CH-, u is 1 ;
provided that when v is 2 or 3, the R2's can be the same or different;
and provided that when u is 2 or 3, the R3's can be the same or
different;
R4 is selected from B-(CH 2 ) m C(0)-, wherein m is 0, 1, 2, 3. 4 or 5;
B-(CH 2 ) q -, wherein q is 0, 1 , 2, 3, 4, 5 or 6;
B-(CH 2 ) e -Z-(CH 2 ) r -, wherein Z is -0-, -C(O)-, phenylene,
-N(R8)- or -8(0)0.2-, e is 0, 1 , 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided
that the sum of e and r is 0. 1 , 2, 3, 4, 5 or 6;
B-(C 2 -C 6 alkenylene)-;
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PCT/US02/01195
B-(C 4 -C 6 alkadienylene)-;
B-(CH 2 ) t -Z-(C 2 -C 6 alkenylene)-, wherein Z is as defined above, and
wherein t is 0, 1 , 2 or 3, provided that the sum of t and the number of carbon
atoms in the alkenylene .chain is 2, 3, 4, 5 or 6;
B-(CH 2 ) r V-(CH 2 ) g -, wherein V is C 3 -C 6 cycloalkylene, f is 1, 2, 3, 4 or
5 and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or
6;
B-(CH 2 ) t -V-(C 2 -C 6 alkenylene)- or
B-(C 2 -C 6 alkenylene)-V-(CH 2 ) ( -, wherein V and t are as defined above,
provided that the sum of t and the number of carbon atoms in the alkenylene
chain is 2, 3, 4, 5 or 6;
B-(CH 2 ) a -Z-(CH 2 ) b -V-(CH 2 ) d -, wherein Z and V are as defined above
and a, b and d are independently 0,1,2, 3, 4, 5 or 6, provided that the sum
of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or
T-(CH 2 ) S -, wherein T is cycloalkyl of 3-6 carbon atoms and s is 0, 1 , 2, 3, 4, 5
R1 and R4 together form the group B-CH=C- ;
B is indanyl. indenyl, naphthyl, tetrahydronaphthyl, heteroaryl or W-substituted
heteroaryl, wherein heteroaryl is selected from the group consisting of: pyrrolyl,
pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl,
oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof,
W is 1 to 3 substituents independently selected from the group consisting of lower
alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy,
alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower
alkyl lower alkanedioyl, allyloxy. -CF 3 , -OCF 3 , benzyl. R7-benzyl, benzyloxy, R7-
benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, N0 2 , -N(Rs)(R9), N(R8)(Rg)-lower
alkylene-, N(R8)(R9)-lower alkylenyloxy-, OH, halogeno, -CN. -N 3> -NHC(O)OR-|0. -
or 6; or
or
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NHC(O)Ri0, R110 2 SNH-, (Rn0 2 S) 2 N-, -S(0) 2 NH 2> -S(0) M R8. tert-butyldimethyl-
silyloxymethyl, -C(0)Ri2. -COOR19, -CON(R8)(R9), -CH=CHC(0)Ri2, -lower
alkylene-C(0)Ri2, Rl()C(0)(lower alkylenyloxy)-. N(R8)(R9)C(0)(lower
and the substituents on the substituted heteroaryl ring nitrogen atoms, when
present, are selected from the group consisting of lower alkyl, lower alkoxy,
-C(0)ORio, -C(0)Rio, OH, N(R8)(R9)-lower alkylene-, N(R8)(R9)-lower
alkylenyloxy-, -S(0) 2 NH 2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower alkyl,
lower alkoxy, -COOH, N0 2 , -N(R8)(R9), OH, and halogeno;
R8 and Rg are independently H or lower alkyl;
R-I0 is lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
R11 is OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-benzyl;
R12 is H, OH, alkoxy, phenoxy, benzyloxy, I \
-N(R8)(Rg). lower alkyl, phenyl or R7-phenyl;
R13 is -0-, -CH 2 -, -NH-, -N(lower alkyl)- or -NC(0)Rig;
R15. R16 and R17 are independently selected from the group consisting of
H and the groups defined for W; or R15 is hydrogen and R-|6 and R17, together
with adjacent carbon atoms to which they are attached, form a dioxolanyi ring;
R-I9 is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of
phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl,
tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl,
benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl,
wherein heteroaryl is as defined above.
One group of preferred compounds of Formula IV is that in which R21 is
phenyl, W-substituted phenyl, indanyl, benzofuranyl, benzodioxolyl,
tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or cyclopropyl,
wherein W is lower alkyl, lower alkoxy, OH, halogeno, -N(R8)(Rg), -NHC(0)ORio,
alkylenyloxy)- and
- CH 2 - N
for substitution on ring carbon atoms,
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17
-NHC(0)Rio, N0 2 , -CN, -N 3 , -SH, ^(O^-flower alkyl). -COOR19, -CON(Rs)(R9),
-COR12, phenoxy, benzyloxy, -OCF 3 , -CH=C(0)R<|2 or tert-butyldimethylsilyloxy,
wherein R8, R9, R10» R12 and R19 are as defined for Formula IV. When W is 2 or
3 substituents, the substituents.can be the same or different.
Another group of preferred compounds of Formula IV is that in which R20 is
phenyl or W-substituted phenyl, wherein preferred meanings of W are as defined
above for preferred definitions of R21 .
More preferred are compounds of Formula IV wherein R20 is phenyl or W-
substituted phenyl and R21 is phenyl, W-substituted phenyl, indanyl, benzofuranyl,
benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl or
cyclopropyl;
wherein W is lower alkyl, lower alkoxy, OH, halogeno,
-N(Rs)(R9), -NHC(0)ORio, -NHC(O)Ri0, N0 2 , -CN, -N 3 , -SH, .S(0)^ 2 -(lower
alkyl), -COOR19, -CON(R8)(R9). -COR12. phenoxy, benzyloxy, -CH=CHC(0)Ri2,
-OCF3 or tert-butyl-dimethyl-silyloxy, wherein when W is 2 or 3 substituents, the
substituents can be the same or different, and wherein Rs, R9, R10, R12 and R19
are as defined in Formula IV.
Another group of preferred compounds of Formula IV is that wherein R2 and
R3 are each -CH 2 - and the sum of u and v is 2, 3 or 4, with u=v=2 being more
preferred.
R4 is preferably B-(CH 2 ) q - or B-(CH 2 ) e -Z-(CH 2 ) r -, wherein B, Z, q, e and r are
hydrogen and wherein R15 is preferably H, OH, lower alkoxy, especially methoxy,
or halogeno, especially chloro.
Preferably Z is -0-, e is 0, and r is 0.
Preferably q is 0-2.
Also preferred are compounds of Formula IV wherein R1 is -CH- or
-C(OH)- .
as defined above. B is preferably
R17 , wherein R16 and R17 are each
WO 02/058696 PCIYUS02/01 195
18
R20 is preferably phenyl or W-substituted phenyl.
Preferred W substrtuents for R20 are lower alkoxy, especially
methoxy and ethoxy, OH, and -C(0)R-|2, wherein R12 is preferably lower alkoxy.
Preferred definitions for R21 are phenyl, lower alkoxy-substituted phenyl and
F-phenyl.
Especially preferred are compounds of Formula IV wherein R1 is -CH- , or
-<t(OH)- , R 2 and R3 are each -CH 2 -, u=v=2, R4 is B-(CH 2 ) q -, wherein B is phenyl
or phenyl substituted by lower alkoxy or chloro, q is 0-2, R20 is phenyl, OH-phenyl,
lower alkoxy-substituted phenyl or lower alkoxycarbonyl-substituted phenyl, and
R21 is phenyl, ower alkoxy-substituted phenyl or F-phenyl.
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formulae (VA) and (VB):
and
(VA)
A
, N
R4
(VB)
or isomers thereof, or pharmaceutically acceptable salts or solvates of the
compounds of Formulas (VA) and (VB) or of the isomers of the compounds of
Formulas (VA) and (VB), or prodrugs of the compounds of Formulas (VA) and (VB)
WO 02/058696 PCT/US02/01195
19
or of the isomers, salts or solvates of the compounds of Formulas (VA) and (VB),
wherein in Formulae (VA) and (VB) above:
A is -CH=CH-, -C"C- or -(CH 2 ) p - wherein p is 0, 1 or 2;
B is
R,
B' is
r
D is -(CH 2 ) m C(0)- or -(CH 2 ) q - wherein m is 1 , 2, 3 or 4 and q is 2, 3 or 4;
E is C10 to C20 alkyi or -C(0)-(Cg to Cig)-alkyl, wherein the alkyl is straight
or branched, saturated or containing one or more double bonds;
R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing
one or more double bonds, or B-(CH 2 ) r -, wherein r is 0, 1 , 2, or 3;
Rli R2> R3. RV. R2\ and R3 1 are independently selected from the group
consisting of hydrogen, lower alkyl, lower alkoxy, carboxy, N0 2 , NH 2 , OH,
halogeno, lower alkylamino, dilower alkylamino, -NHC(0)OR5, R60 2 SNH- and
-S(0) 2 NH 2 ;
R4 is
fj ^(OR 5 )n
wherein n is 0, 1, 2 or 3;
R5 is lower alkyl; and
R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl wherein the
substituents are 1-3 groups independently selected from the group consisting of
lower alkyl, lower alkoxy, carboxy, N0 2 , NH 2 , OH, halogeno, lower alkylamino and
dilower alkylamino.
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Preferred are compounds of Formula (VA) wherein R is hydrogen, saturated
or mono-unsaturated Ci -C10 alkyl or phenyl. Another group of preferred
compounds of Formula (VA) is that wherein D is propyl (i.e., -(CH 2 ) q - and q is 3). A
third group of preferred compounds of Formula (VA) is that wherein R4 is p-
methoxyphenyi or 2,4,6-trimethoxyphenyl. Still another group of preferred
compounds of Formula (VA) is that wherein A is ethylene or a bond (i.e., -(CH 2 ) -
wherein p is zero). Ry, R?. and R3' are preferably each hydrogen, and preferably
R1 is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-butoxycarbonyl-amino and
R2 and R3 are each hydrogen.
Especially preferred are compounds of Formula (VA) wherein Ry, R?, and
R3' are each hydrogen; R1 is hydrogen, hydroxy, nitro, lower alkoxy, amino or t-
butoxycarbonyl-amino and R2 and R3 are each hydrogen; R is hydrogen, ethyl or
phenyl; D is propyl; R4 is p-methoxyphenyl or 2,4,6-trimethoxyphenyl; and A is
ethylene or a bond.
Preferred compounds of Formula (VA), wherein B' is phenyl, are shown in
the following table:
WO 02/058696 PCT/US02/01195
21
D
R
A
B
R4
-(CH 2 ) 3 -
H
p-MeO-
phenyl
p-MeO-phenyl
-CH 2 C(0)-
phenyl
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
H
—
phenyl
p-MeO-phenyl
H
p-OH-
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
H
ethylene
p-MeO-
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
H
3-MeO-
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
ethyl
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
phenyl
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
ethyl
phenyl
2,4,6-tri-MeO-
phenyl
-(CH 2 ) 3 -
methyl
phenyl
p-MeO-phenyl
-(CH 2 ) 3 -
H
p-NH 2 -
phenyl
p-MeO-phenyl
The first-listed compound in the above table having the (3R,4S) absolute
stereochemistry is more preferred.
5 Preferred compounds of Formula (VB) are those wherein R is hydrogen,
methyl, ethyl, phenyl or phenylpropyl. Another group of preferred compounds of
Formula (VB) is that wherein R4 is p-methoxyphenyl or 2,4,6-trimethoxyphenyl.
Still another group of preferred compounds of Formula (VB) is that wherein A is
ethylene or a bond. Yet another group of preferred compounds of Formula (VB) is
10 that wherein E is decyl, oleoyl or 7-Z-hexadecenyl. Preferably Ri ( R2 and R3 are
each hydrogen.
Especially preferred compounds of Formula (VB) are those wherein R is
hydrogen, methyl, ethyl, phenyl or phenylpropyl; R4 is p-methoxyphenyl or 2,4,6-
WO 02/058696
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22
trimethoxyphenyl; A is ethylene or a bond; E is decyl, oleoyl or 7-Z-hexadecenyl;
and Ri, R2 and R3 are each hydrogen.
An especially preferred compound of Formula (VB) is that wherein E is
decyl, R is hydrogen, B-A is phenyl and R4 is p-methoxyphenyl.
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formula (VI):
or isomers thereof, or pharmaceutically acceptable salts or solvates of the
compounds of Formula (VI) or of the isomers of the compounds of Formula (VI), or
prodrugs of the compounds of Formula (VI) or of the isomers, salts or solvates of
the compounds of Formula (VI),
wherein in Formula (VI):
R 26 isHor OG 1 ;
G and G 1 are independently selected from the group consisting of
(VI)
H.
CQ 2 R 2
PR 4
-1IOR 3
CH 2 OR 6
PR 4
•"I OR 3 , - CH 2
OR 7
OR 4
•0IOR 5
OR 3
OR
and
provided that when R 26 is H or
OH, G is not H;
R, R a and R D are independently selected from the group consisting of H, -
OH. halogeno, -NH 2 , azido, (C 1 -C 6 )alkoxy(C 1 -C 6 )-alkoxy or -W-R30;
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W is independently selected from the group consisting of
-NH-C(Oh -O-C(O)-, -0-C(0)-N(R 31 )-, -NH-C(0)-N(R 31 )- and
-0-C(S)-N(R 31 )-;
R 2 and R& are independently selected from the group consisting of H, (C r
C 6 )alkyl, aryl and aryl(C r C 6 )alkyl;
R 3 , R 4 , R 5 , R 7 , R 3a and R 4a are independently selected from the group
consisting of H, (C r C 6 )alkyI, aryl(C r C 6 )alkyl, -C(0)(C r C 6 )alkyl and -C(0)aryl;
R 30 is selected from the group consisting of R 32 -substituted T, R 32 -
substituted-T-(C r C 6 )alkyl, R 32 -substituted-(C 2 -C 4 )alkenyl, R 32 -substituted-(C r
C 6 )alkyl, R 32 -substituted-(C 3 -C 7 )cydoaIkyl and R 32 -substituted-(C 3 -
CyJcycloalkyKC^C^alkyl;
R 31 is selected from the group consisting of H and (C 1 -C 4 )alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,
imidazolyl and pyridyl;
R 32 is independently selected from 1-3 substituents independently selected
from the group consisting of halogeno, (C r C 4 )alkyl, -OH, phenoxy, -CF 3 , -N0 2? (C-,-
C 4 )alkoxy, methylenedioxy, oxo, (C^-CJalkylsulfanyl, (C r C 4 )alkylsulfinyI, (C r
C 4 )alkylsulfonyl, -N(CH 3 ) 2 , -C(0)-NH(C 1 -C 4 )alkyl t -C(0)-N((C 1 -C 4 )alkyl) 2f -C(OHC r
C 4 )alkyl, -C(0)-(C r C 4 )alkoxy and pyrrolidinylcarbonyl; or R 32 is a covalent bond
and R 31 , the nitrogen to which it is attached and R 32 form a pyrrolidinyl,
piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C r
CJalkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl
or morpholinyl group;
Ar1 is aryl or R 1 0-substituted aryl;
Ar 2 is aryl or R 1 1 -substituted aryl;
Q is a bond or, with the 3-position ring carbon of the azetidinone,
R 1 ?— (R 13 )
a
; and
WO 02/058696 PCT/US02/0 1 1 95
24
R 1 is selected from the group consisting of
-(CH 2 ) q -, wherein q is 2-6, provided that when Q forms a spiro ring, q
can also be zero or 1 ;
-(CH 2 ) e -E-(CH 2 ) r -, wherein E is -O-, -C(O)-, phenylene, -NR22. or -
S(C /0 _ 2 -, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C 2 -C 6 )alkenylene-; and
-(CH 2 ) r V-(CH 2 ) g -, wherein V is C 3 -C 6 cycloalkylene, f is 1-5 and g is
0-5, provided that the sum of f and g is 1-6;
Rl2j s
II ill ||
-CH-, -C(C r C 6 alkyl)-. -CF-, -C(OH)-, -C(C 6 H 4 -R 23 )-, -N-, or --NO' ;
R 13 and R 14 are independently selected from the group consisting of -CH 2 -, -
CH(C,-C 6 alkyl)-, -C(di-(C 1 -C 6 ) alkyl), -CH=CH- and -C(C r C 6 alkyl)=CH-; or R12
together with an adjacent R 13 , or R 1 2 together with an adjacent R 14 , form a -
CH=CH- or a -CH=C(C 1 -C 6 alkyl)- group;
a and b are independently 0, 1 , 2 or 3, provided both are not zero;
provided that when R 13 is -CH=CH- or -C(C,-C 6 alkyl)=CH-, a is 1 ;
provided that when R14 is -CH=CH- or -C(C r C 6 alkyl)=CH-, b is 1;
provided that when a is 2 or 3, the R 13 's can be the same or different; and
provided that when b is 2 or 3, the R 14 's can be the same or different;
and when Q is a bond, R 1 also can be:
R15 R 17 R15 R 15
-M-Y d -C-Z t1 -,-X m -(C) s -Y n -(C) t -Z p - or -X r (C) v -Y k -S(0)o. 2 -;
R 16 rib r16 R 16
M is -0-, -S-. -S{0)- or -S(0) 2 -;
X, Y and Z are independently selected from the group consisting of -CH 2 -,
-CH(C r C 5 )alkyl- and -C(di-(C r C 6 )alkyl);
R 10 and R 1 1 are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of (C^C^alkyl,
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25
-OR 1 9, -0(CO)R 19 , -0(CO)OR21, -OCCH^^ORlS, -O(CO)NR 1 9r20, .NRl9R20 f
-NR 1 9(CO)R20, -NR19(C0)0R21, -NR 1 9(CO)NR20r25 > -NR19s0 2 R21,
-COOR 19 , -CONR19R20, -COR19, -SO 2 NR19r20 i S(0)o. 2 r21,
-OtCHj^o-COOR^, -O(CH 2 )' 1 . 10 CONR 1 9r20 ) -(C,-C 6 alkylene)-COORl9 t
-CH=CH-COOR 1 9, -CF 3 , -CN, -N0 2 and halogen;
R 1 ^ and R 17 are independently selected from the group consisting of
-OR 1 9, -0(C0)R19, -0(CO)OR21 and -O(CO)NR19r20 ;
R 16
and R 18 are independently selected from the group consisting of H,
(C r C 6 )alkyl and aryl; or R 15 and R 16 together are =0, or R 17 and R 18 together
are =0;
d is 1 , 2 or 3;
hisO, 1,2, 3 or 4;
s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4;
provided that at least one of s and t is 1 , and the sum of m, n, p, s and t is 1-
6;
provided that when p is 0 and t is 1 , the sum of m, s and n is 1-5; and
provided that when p is 0 and s is 1 , the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
R 15
-X r (C) v -Y k -S(0)o. 2 -
and when Q is a bond and R 1 is R 16 , Ar 1 can also be
pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl,
pyrimidinyl or pyridazinyl;
R 19 and R 2 ^ are independently selected from the group consisting of H,
(C r C 6 )alkyl, aryl and aryl-substituted (C r C 6 )alkyl;
R 21 is (C r C 6 )alkyl, aryl or R 24 -substituted aryl;
R 22 is H, (C r C 6 )alkyl, aryl (C r C 6 )alkyl, -C(0)R19 or-COORl9;
WO 02/058696 PCMJS02/01 195
26
R23 and R24
are independently 1-3 groups independently selected from the
group consisting of H, (C r C 6 )aIkyl, (C^C^alkoxy, -COOH, N0 2 , -NR19r20, _oh
and halogeno; and
R 25 is H, -OH or (C^C^alkoxy.
Ar 2 is preferably phenyl or R 11 -phenyl, especially (4-R 1 1 ^substituted
phenyl. Preferred definitions of R 1 1 are lower alkoxy, especially methoxy. and
halogeno, especially fluoro.
Ar 1 is preferably phenyl or R 10 -substituted phenyl, especially (4-R 10 )-
substituted phenyl. A preferred definition of R 10 is halogeno, especially fluoro.
There are several preferred definitions for the -R1-Q- combination of
variables:
Q is a bond and R^ is lower alkylene, preferably propylene;
Q is a spiro group as defined above, wherein preferably R 13 and R 14 are
i i
each ethylene and R 12 is -CH- or -C(OH)- t an d R^is -(CH 2 ) q wherein q is 0-6;
R 15
Q is a bond and R 1 is " M ~Y d -C - Z^— wherein the variables
R 16
are chosen such that R 1 is -0-CH 2 -CH(OH)-;
R 17 R 1 5
Q is a bond and R 1 _x m -(C) s -Y n -(C) t -Zp- wherein the
is R 18 r16
variables are chosen such that R 1 is -CH(OH)-(CH 2 ) 2 -; and
R 15
Q is a bond and R 1 is -Xj-(C) v -Y k -S(0)o. 2 - wherein the
R 16
variables are chosen such that R 1 is -CH(OH)-CH 2 -S(O) 0 . 2 -.
A preferred compound of Formula (VI) therefore, is one wherein G and G 1
are as defined above and in which the remaining variables have the following
definitions:
Ar 1 is phenyl or R 10 -substituted phenyl, wherein R 10 is halogeno;
WO 02/058696 PCT/US02/01 195
27
Ar 2 is phenyl or R 1 1 -phenyl, wherein R 1 1 is 1 to 3 substituents
independently selected from the group consisting of C,-C 6 alkoxy and halogeno;
Q is a bond and R 1 is lower alkylene; Q, with the 3-position
\l2_ (R 13 )a
ring carbon of the azetidinone, forms the group ( r1 \ wherein preferably
R 13 and R 14 are each ethylene and a and b are each 1, and wherein R 12 is
i i
-CH- or -C(OH)- ; Q is a bond and R 1 is -0-CH 2 -CH(OH)-; Q is a bond and R 1 is
-CH(OH)-(CH 2 ) 2 -; or Q is a bond and R 1 is -CH(OH)-CH 2 -S(O) 0 . 2 -.
Preferred variables for G and G 1 groups of the formulae
OR 5 OR 4 OR 4 OR 7
-/~\»iOR 3 — (~\-»>OR 2 and -CH2-/~\-iOR 5
0 "\o 2 R 2 ^H 2 OR 6 ^ R 3 OR 4
are as follows:
R 2 , R3 t R4 t R5 t r6 anc j r7 a re independently selected from the group
consisting of H, (C^C^alkyl, benzyl and acetyl.
Preferred variables for group G or G 1 of the formula
OR 3a
R 4a a. JfR
OR* A 0 ^CH 2 R b
^O^CH 2 R a
are as follows:
R 3 , R3a t r4 and R 4a are selected from the group consisting of H, (C,-
C 6 )alkyl, benzyl and acetyl;
R, R a and R D are independently selected from the group consisting of H, -
OH, halogeno, -NH 2 , azido, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy and -W-R 30 , wherein W is •
O-C(O)- or-O-C(0)-NR31-, R31 j s H and R 3 0 is (C^C^alkyl, -C^HC^Jalkoxy-
(C^C^alkyl, T . T-(C 1 -C 6 )alkyl, or T or T-^-C^alkyl wherein T is substituted by
one or two halogeno or (C,-C 6 )alkyl groups.
WO 02/058696
PCT/US02/01195
28
Preferred R 30 substituents are selected from the group consisting of 2-
fluorophenyl, 2,4-difluoro-phenyl, 2,6-dichlorophenyI, 2-methylphenyl, 2-
thienylmethyi, 2-methoxy-carbonylethyl, thiazol-2-y!-methyl, 2-furyl, 2-
Preferred combinations of R, R a and R b are as follows:
1) R, R a and R b are independently -OH or -O-C(O)-NH-R30 f
especially wherein R a is -OH and R and R b are -0-C(0)-NH-R 30 and R 30 is
selected from the preferred substituents identified above, or wherein R and
R a are each -OH and Rb is-O-C(O)-NH-R 3 0 wherein R 30 is 2-fluorophenyl,
2,4-difluoro-phenyl, 2,6-dichlorophenyl;
2) R a is -OH, halogeno, azido or (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy t R b is
H, halogeno, azido or (C r C 6 )alkoxy(C r C 6 )-a!koxy, and R is -0-C(0)-NH-
R 30 , especially compounds wherein R a is -OH, R b is H and R 30 is 2-
fluorophenyl;
3) R, R a and R b are independently -OH or -0-C(0)-R 30 and R 30 is
(C^C^alkyl, T , or T substituted by one or two halogeno or (C^^alkyl
groups, especially compounds wherein R is -OH and R a and R b are
-0-C(0)-R 30 wherein R 3 0 is 2-furyl; and
4) R, R a and R b are independently -OH or halogeno. Three
additional classes of preferred compounds are those wherein the C 1 '
anomeric oxy is beta, wherein the C 2? anomeric oxy is beta, and wherein the
R group is alpha.
G and G 1 are preferably selected from:
methoxycarbonylbutyl and phenyl.
WO 02/058696
PCT/US02/01195
29
,OCH 3
OH
•llOH
OAc
X> Ac
0 -J*CH 2 OAc
HO/,
and
HO/,
0 F v
oh n K1 >=\
A 0 A C H 2 0H
HO
CH 2 OH
wherein Ac is acetyl and Ph is phenyl.
Preferably, R26 is H or OH, more preferably H. The -O-G substituent is
preferably in the 4-position of the phenyl ring to which it is attached.
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formula (VII):
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (VII) or of the isomers of the compounds of Formula (VII),
or prodrugs of the compounds of Formula (VII) or of the isomers, salts or solvates
of the compounds of Formula (VII),
wherein in Formula (VII) above:
(VII)
WO 02/058696 PCT/US02/01195
30
Ar 1 and Ar 2 are independently selected from the group consisting of aryl
and R 4 -substituted aryl;
Ar 3 is aryl or R 5 -substituted aryl;
X. Y and Z are independently selected from the group consisting of -CH 2 -,
-CH(lower alkyl)- and -C(dilower alkyl)-;
R and R 2 are independently selected from the group consisting of -OR 6 ,
-0(CO)R6, -0(CO)OR9 and -0(CO)NR 6 r7 ;
R 1 and R3 are independently selected from the group consisting of
hydrogen, lower alkyl and aryl;
q is 0 or 1 ; r is 0 or 1 ; m, n and p are independently 0. 1 , 2, 3 or 4; provided
that at least one of q and r is 1 , and the sum of m, n, p, q and r is 1 , 2, 3, 4, 5 or 6;
and provided that when p is 0 and r is 1 , the sum of m, q and n is 1 , 2, 3, 4 or 5;
R 4 is 1-5 substituents independently selected from the group consisting of lower
alkyl, -OR6, -0(CO)R 6 , -0(CO)OR9, -OfCH^OR 6 -0(CO)NR 6 r7, -NR6r7
-NR6(CO)R/\ -NR6(CO)OR9, -NR6(CO)NR7r8, -NR6so 2 R 9 , -COOR 6
-CONR6R7, _cor6 -S0 2 NR6r7, 8(0)^9, -OfChy^-COORe,
-O(CH 2 ) 1 . 10 CONR6r7 > -(lower alkylene)COOR6, -CH=CH-COOR6, -CF 3 , -CN,
-N0 2 and halogen;
R 5 is 1-5 substituents independently selected from the grcup consisting of -OR 6 ,
-0(CO)R6, -0(CO)OR9, -0(CH 2 ) 1 . 5 OR6, -0(CO)NR6r7, -NR6R7, . N r6(CO)R7,
-NR6(CO)OR9, -NR6(CO)NR7r8, -NR6s0 2 R9, -COOR 6 , -CONR6R7, . C OR 6 t
-S0 2 NR6R7, 8(0)^9, -O(CH 2 ) 1 . 10 -COOR6, ^(CH.J^^CONRBrT,
-(lower alkylene)COOR 6 and -CH=CH-COOR 6 ;
R 6 , R 7 and R 8 are independently selected from the group consisting of
hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R 9 is lower alkyl, aryl or aryl-substituted lower alkyl.
R 4 is preferably 1-3 independently selected substituents, and R5 j s
preferably 1-3 independently selected substituents.
WO 02/058696
31
PCT/US02/01195
Preferred compounds of Formula (VII) are those in which Ar1 is phenyl or
R 4 -substituted phenyl, more preferably (4-R 4 )-substituted phenyl. Ar 2 is preferably
phenyl or R 4 -substituted phenyl, more preferably (4-R 4 ^substituted phenyl. An* is
preferably R 5 -substituted phenyl, more preferably (4-R 5 )-substituted phenyl. When
Ar 1 is (4-R 4 ^substituted phenyl, R 4 is preferably a halogen. When Ar 2 and An*
are R 4 - and R 6 -substituted phenyl, respectively, R 4 is preferably halogen or -OR 6
and R 5 is preferably -OR 6 , wherein R 6 is lower alkyl or hydrogen. Especially
preferred are compounds wherein each of Ar 1 and Ar 2 is 4-fluorophenyl and Ar* is
4-hydroxyphenyl or 4-methoxyphenyl.
X, Y and Z are each preferably -CH 2 -. R 1 and R 3 are each preferably
hydrogen. R and R 2 are preferably -OR 6 wherein R 6 is hydrogen, or a group
readily metabolizable to a hydroxyl (such as -0(CO)R 6 , -0(CO)OR 9 and
-0(C0)NR 6 R7, defined above).
The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.
Preferred are compounds wherein m, n and r are each zero, q is 1 and p is 2.
Also preferred are compounds of Formula (VII) wherein p, q and n are each
zero, r is 1 and m is 2 or 3. More preferred are compounds wherein m, n and r are
each zero, q is 1 , p is 2, Z is -CH 2 - and R is -OR 6 , especially when R 6 is hydrogen.
Also more preferred are compounds of Formula (VII) wherein p, q and n are
each zero, r is 1 , m is 2, X is -CH 2 - and R 2 is -OR 6 , especially when R 6 is
hydrogen.
Another group of preferred compounds of Formula (VII) are those wherein,
Ar 1 is phenyl or R 4 -substituted phenyl, Ar 2 is phenyl or R 4 -substituted phenyl and
Ar 3 is R 5 -substituted phenyl. Also preferred are compounds wherein Ar 1 is phenyl
or R 4 -substituted phenyl, Ar 2 is phenyl or R 4 -substituted phenyl, Ar 3 is R 5 -
substituted phenyl, and the sum of m, n, p, q and r is 2, 3 or 4, more especially 3.
More preferred are compounds wherein Ar 1 is phenyl or R 4 -substituted phenyl, Ar 2
is phenyl or R 4 -substituted phenyl, Ar 3 is R 5 -substituted phenyl, and wherein m, n
and r are each zero, q is 1 and p is 2, or wherein p, q and n are each zero, r is 1
and m is 2 or 3.
WO 02/058696 PCT7US02/01 195
32
In a preferred embodiment, a sterol absorption inhibitor and/or stanol
absorption inhibitor of Formula (VII) useful in the compositions, combinations and
methods of the present invention is represented by Formula (VIII) (ezetimibe)
below:
(VIII)
or pharmaceutical^ acceptable salts or solvates of the compounds of Formula
(VIII), or prodrugs of the compound of Formula (VIII) or of the salts or solvates of
the compound of Formula (VIII).
In another embodiment, one or more sterol absorption inhibitors and/or
stanol absorption inhibitors useful in the methods, compositions or combinations of
this invention are represented by Formula (IX):
or isomers of the compounds of Formula (IX), or pharmaceutical^ acceptable salts
or solvates of the compounds of Formula (IX) or of the isomers of the compounds
of Formula (IX), or prodrugs of the compounds of Formula (IX) or of the isomers,
salts or solvates of the compounds of Formula (IX),
wherein in Formula (IX) above:
R26 i S selected from the group consisting of:
a) OH;
b) OCH 3 ;
c) fluorine and
WO 02/058696 PCT/US02/01 195
33
d) chlorine.
R 1 is selected from the group consisting of
OR 5 OR 4 OR 5 OR 4 / 0R?
^— c ^r—r O— <
H,
_-(J).„IOR 3 , _(~\.„ior 3 , -CH 2 -^_)'.HOR 5
°"\o 2 r 2 °"\h 2 or 6 6v or4
OR 3a
R -S0 3 H; natural and unnatural
O!
R«0/, T
OR 3 0 ^o CH 2 Rb amino acids.
^ 0 ^CH 2 R a
R, R a and R D are independently selected from the group consisting of H,
-OH, halogeno, -NH 2> azido, (C 1 -C 6 )alkoxy(C 1 -C 6 )-alkoxy and -W-R 30 ;
W is independently selected from the group consisting of
-NH-C(O)-, -O-C(O)-, -0-C(0)-N(R31 .NH-C(0)-N(R31 y and
-0-C(S)-N(R31)-;
R2 and R^ are independently selected from the group consisting of H, (Ci-
C6)alkyl, aryl and aryl(Ci-C6)alkyl;
R 3 , R 4 , R 5 , R 7 , R 3a and R 4a are independently selected from the group
consisting of H, (CVC^alkyl, aryKC^C^alkyl, -CfOXC^C^alkyl and -C(0)aryl;
R 3 ^ is independently selected from the group consisting of
R 3 2-substituted T, R 3 2-substituted-T-(C 1 -C 6 )alkyl, R 3 2- S ubstituted-(C 2 -C 4 )alkenyl,
R32. su bstituted-(C 1 -C 6 )alkyl, R 3 2-substituted-(C 3 -C 7 )cycloalkyl and R 32 -
substituted-(C 3 -C 7 )cycloalkyl(C r C 6 )alkyl;
R 31 is independently selected from the group consisting of H and (C.,-
C 4 )alkyl;
T is independently selected from the group consisting of phenyl, furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl,
thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
WO 02/058696 PCT/US02/01195
34
R 32 is independently selected from 1-3 substituents independently selected
from the group consisting of H, halogeno, (C r C 4 )alkyl, -OH, phenoxy, -CF 3 , -N0 2 ,
(C r C 4 )alkoxy, methylenedioxy, oxo, (C r C 4 )alkylsulfanyl, (C r C 4 )alkylsulfinyl,
(C r C 4 )alkylsulfonyl, -N(CH 3 ) 2 , rC(0>-NH(C r C 4 )alkyl t -C(O^N((C r C 4 )alkyl) 2 ,
-C(0)-(C r C 4 )alkyl, -C(0)-(C r C 4 )alkoxy and pyrrolidinylcarbonyl; or R32 j s a
covalent bond and R 31 , the nitrogen to which it is attached and R 32 form a
pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a
(C r C 4 )alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl,
indolinyl or morpholinyl group;
Ar 1 is aryl or R^O-substituted aryl;
Ar 2 is aryl or R 1 1 -substituted aryl;
Q is -(CH 2 ) q -, wherein q is 2-6, or, with the 3-position ring carbon of the
azetidinone,
forms the spiro group ;
Rl2 is
ll ill ||
-CH-, -C(C r C 6 alkyl)-, -CF-, -C(OH)-, -C(C 6 H 4 -R 23 )-, -N-. or- + NO" ;
R 13 and R™ are independently selected from the group consisting of -CH 2 -,
-CH(C r C 6 alkyl)-, -C^HC^C,.) alkyl), -CH=CH- and -C(C r C 6 alkyl)=CH-; or R12
together with an adjacent R" 13 , or R 12 together with an adjacent R14 ? form a
-CH=CH- or a -CH=C(C 1 -C 6 alkyl)- group;
a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided
that when R 13 is -CH=CH- or -C{C,-C 6 alkyl)=CH-, a is 1 ; provided that when R 1 *
is -CH=CH- or -C{C V C 6 alkyl)=CH-, b is 1; provided that when a is 2 or 3, the
R 13 's can be the same or different; and provided that when b is 2 or 3, the R 14 's
can be the same or different;
R 10 and R 1 1 are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of (C^-C^alkyl,
WO 02/058696
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35
-OR 19 , -0(CO)Rl9 -0(CO)OR21, -OCCH^^ORlQ, .O(CO)NR19r20 j .MR19R20,
-NR19(CO)R20, -NR19(C0)0R21 | -NR 1 9(CO)NR20R25 f -NR19s0 2 R 2 1,
-COOR19, -CONR 1 9r20 | -COR19, .SO 2 NRl9R20 f S(O ) 0 2 R21 f
-©(CH^^-COOR^, -O(CH 2 ) 1 . 10 CONR19r20 > _( Cr C 6 alkylene)-COORl9 f
-CH=CH-COOR 19 , -CF 3 , -CN, -N0 2 and halogen;
Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl,
pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R 19 and R 20 are independently selected from the group consisting of H.
(C r C 6 )alkyl, aryl and aryl-substituted (C r C 6 )alkyl;
R 21 is (C r C 6 )alkyI, aryl or R 24 -substituted aryl;
R 22 is H, (C r C 6 )alkyl, aryl (C r C 6 )alkyl, -C(0)R19 or-COORl 9 ;
R 23 and R 24 are independently 1-3 groups independently selected from the
group consisting of H, (C r C 6 )alkyl t (C r C 6 )alkoxy, -COOH, N0 2 , -NR1 9 R 2 0, -OH
and halogeno; and
R 25 is H, -OH or (C r C 6 )alkoxy.
Ar 2 is preferably phenyl or R 1 1 -phenyl, especially (4-R 1 ^substituted
phenyl. Preferred definitions of R 1 1 are lower alkoxy, especially methoxy, and
halogeno, especially fluoro.
Ar 1 is preferably phenyl or R 10 -substituted phenyl, especially (4-R 10 )-
substituted phenyl. A preferred definition of R 10 is halogeno, especially fluoro.
Preferably Q is a lower alkyl or a spiro group as defined above, wherein
i i
preferably R 13 and R 14 are each ethylene and R 12 is -CH- or -C(OH)- .
A preferred compound of formula IX, therefore, is one wherein R 1 is as
defined above and in which the remaining variables have the following definitions:
Ar 1 is phenyl or R 1 ^substituted phenyl, wherein R 10 is halogeno;
Ar 2 is phenyl or R 11 -phenyl, wherein R 11 is 1 to 3 substituents
independently selected from the group consisting of C^Cg alkoxy and halogeno;
WO 02/058696
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36
Q is a lower alkyl (i.e. C-1 to C-2) with Q = C-2 being preferred, or Q, with
the 3-position ring carbon of the azetidinone, forms the group (R 14 )b —
wherein preferably R13 and R 14 are each ethylene and a and b are each 1, and
are as follows:
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from the group
consisting of H, (C^C^alkyl, benzyl and acetyl.
Preferred variables for group R 1 of the formula
OR 3a
are as follows:
R 3 , R 3a , R 4 and R 4a are selected from the group consisting of H,
(C 1 -C 6 )alkyl, benzyl and acetyl;
R, R a and R b are independently selected from the group consisting of H,
-OH, halogeno, -NH 2 , azido, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy and -W-R 3 0, wherein W is
-O-C(O)- or-0-C(0)-NR 3 1-, R 3 1 is H and R 3 ° is (C r C 6 )alkyl. -C(OHC 1 -C 4 )alkoxy-
(C r C 6 )alkyl, T , T-(C 1 -C 6 )alkyl, or T or T-(C n -C 6 )alkyl wherein T is substituted by
one or two halogeno or (C r C 6 )alkyl groups.
Preferred R 30 substituents are 2-fluorophenyl, 2,4-difluoro-phenyl, 2,6-
dichlorophenyl, 2-methylphenyl, 2-thienylmethyl, 2-methoxy-carbonylethyl,
thiazol-2-yl-methyl, 2-furyl, 2-methoxycarbonylbutyl and phenyl. Preferred
combinatio-s of R, R a and R D are as follows: 1) R, R a and Rb are independently -
wherein R12 j s -CH- or -C(OH)- ;
Preferred variables for R 1 groups of the formula
O^DR 4 OF* OR 4
— ( ViOR 3 — ( \-iqr 3 and -Ci
.-■OR 5
WO 02/058696
PCT/US02/01195
OH or -0-C(0)-NH-R 30 , especially wherein R a is -OH and R and R b are -O-C(O)-
NH-R 30 and R 30 is selected from the preferred substituents identified above, or
wherein R and Ra are -OH and R b is-O-C(O)-NH-R 3 0 wherein R 30 is 2-
fluorophenyl, 2,4-difIuoro-phenyl, 2,6-dichlorophenyl; 2) R a is -OH, halogeno,
5 azido or (C^C^-alkoxytC^CgJalkoxy, R D is H, halogeno, azido or (C 1 -C 6 )alkoxy(C 1 -
C 6 )-alkoxy, and R is
-0-C(0)-NH-R 30 , especially compounds wherein R a is -OH, R D is H and R 30 is
2-fluorophenyl; 3) R, R a and R D are independently -OH or-0-C(0)-R 30 and R 30
is (0,-C 6 )alkyl, T , orT substituted by one or two halogeno or (C,-C 6 )alkyl groups,
10 especially compounds wherein R is -OH and R a and R D are -0-C(0)-R 30 wherein
r30 i s 2-furyl; and 4) R, R a and R D are independently -OH or halogeno. Three
additional classes of preferred are compounds are those wherein the C''' anomeric
oxy is beta, wherein the C^' anomeric oxy is beta, and wherein the R group is
alpha.
15 R 1 is preferably selected from:
OH 0H OH OH o-^° H ^> 0Ac
-/)'HOH ,— (YllOH , -CH 2 -T~\'l|OH , -^~\.||OAc
20
WO 02/058696
PCT/US02/01195
38
OH OAc
HQfc JUP H A <%. Xs\ OAc
OH ^o^C^OH OAc X 0 i»CH 2 OAc
Hty X*P U , AcO/,. JUP
•Xo^CH20H -Xq^cHjOAc
OH I' >=\
and OH AJ*CH 2 OH
HO r£
•^O ^CH 2 OH
wherein Ac is acetyl and Ph is phenyl.
Thus a preferred compound of this invention is one represented by the
Formula (X):
(X)
or pharmaceutical^ acceptable salts or solvates of the compound of Formula (X),
or prodrugs of the compound of Formula (X) or of the salts or solvates of the
compound of Formula (X), wherein R 1 is defined as above.
A more preferred compound is one represented by Formula (XI):
(XI)
WO 02/058696 PCT/US02/01 195
39
or pharmaceutical^ acceptable salts or solvates of the compound of Formula (XI),
or prodrugs of the compound of Formula (XI) or of the salts or solvates of the
compound of Formula (XI).
Methods for making the compounds described above and other non-limiting
examples of suitable compounds useful in the present invention are disclosed in
U.S. Patents Nos. 5,767,115; 5,846,966; 5,756,470, 5,698,548; 5,624,920;
5,656,624; 5,688,787; 5,688,990, 5,631,365, 6,207,822 and U.S. Provisional Patent
Application 60/279,288 filed March 28, 2001, each of which is incorporated herein
by reference.
Generally, compounds of Formulae l-XI can be prepared by known methods,
for example WO 93/02048 describes the preparation of compounds wherein -R 1 -Q-
is alkylene, alkenylene or alkylene interrupted by a hetero atom, phenylene or
cycloalkylene; WO 94/17038 describes the preparation of compounds wherein Q is
a spirocyclic group; WO 95/08532 describes the preparation of compounds
wherein -R 1 -Q- is a hydroxy-substituted alkylene group; PCT/US95/03196
describes compounds wherein -R1-Q- is a hydroxy-substituted alkylene attached to
the Ar 1 moiety through an -O- or S(0)o-2- group; and U.S. Serial No. 08/463,619,
filed June 5, 1995, describes the preparation of compounds wherein -R^-Q- is a
hydroxy-substituted alkylene group attached the azetidinone ring by a -S(O)0-2-
group, each of which is incorporated herein by reference.
As used herein, the term "alky!" or lower alkyl M means straight or branched
alkyl chains of 1 to 6 carbon atoms and "alkoxy" similarly refers to alkoxy groups
having 1 to 6 carbon atoms. Non-limiting examples of suitable lower alkyl groups
include methyl, ethyl, propyl and butyl groups.
"Alkenyl" means straight or branched carbon chains having one or more
double bonds in the chain, conjugated or unconjugated. Similarly, "alkynyl" means
straight or branched carbon chains having one or more triple bonds in the chain.
Where an alkyl, alkenyl or alkynyl chain joins two other variables and is therefore
bivalent, the terms alkylene, alkenylene and alkynylene are used.
"Cycloalkyl" means a saturated carbon ring of 3 to 6 carbon atoms, while
"cycloalkylene" refers to a corresponding bivalent ring, wherein the points of
attachment to other groups include all positional isomers.
WO 02/058696
40
PCT/US02/01195
"Halogeno" refers to fluorine, chlorine, bromine or iodine radicals.
"AryT means phenyl, naphthyl, indenyl, tetrahydronaphthyl or indanyl.
"Phenylene" means a bivalent phenyl group, including ortho, meta and
para-substitution.
5 The statements wherein, for example, R 19 , R 20 and R 25 are said to be
independently selected from a group of substituents, means that R 19 , R 2 0 and R 2 ^
are independently selected, but also that where an R 19 , R 20 or R 25 variable
occurs more than once in a molecule, those occurrences are independently
selected (e.g., if R 10 is -OR 19 wherein R 19 is hydrogen, R 1 1 can be -OR 19
10 wherein R^ 9 is lower alkyl). Those skilled in the art will recognize that the size and
nature of the substituent(s) will affect the number of substituents which can be
present.
Compounds of the invention have at least one asymmetrical carbon atom
and therefore all isomers, including enantiomers, stereoisomers, rotamers,
15 tautomers, racemates of the compounds of Formula (l-XI) (where they exist) are
contemplated as being part of this invention. The invention includes d and I
isomers in both pure form and in admixture, including racemic mixtures. Isomers
can be prepared using conventional techniques, either by reacting optically pure or
optically enriched starting materials or by separating isomers of a compound of the
20 Formulae l-XI. Isomers may also include geometric isomers, e.g., when a double
bond is present.
Those skilled in the art will appreciate that for some of the compounds of the
Formulas l-XI, one isomer will show greater pharmacological activity than other
isomers.
25 Compounds of the invention with an amino group can form pharmaceutical^
acceptable salts with organic and inorganic acids. Examples of suitable acids for
salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,
salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other
mineral and carboxylic acids well known to those in the art. The salt is prepared by
30 contacting the free base form with a sufficient amount of the desired acid to
produce a salt. The free base form may be regenerated by treating the salt with a
suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate.
The free base form differs from its respective salt form somewhat in certain
WO 02/058696
41
PCT/US02/01195
physical properties, such as solubility in polar solvents, but the salt is otherwise
equivalent to its respective free base forms for purposes of the invention.
Certain compounds of the invention are acidic (e.g., those compounds which
possess a carboxyl group). These compounds form pharmaceutical^ acceptable
salts with inorganic and organic bases. Examples of such salts are the sodium,
potassium, calcium, aluminum, gold and silver salts. Also included are salts formed
with pharmaceutical^ acceptable amines such as ammonia, alkyl amines,
hydroxyalkylamines, N-methylglucamine and the like.
As used herein, "prodrug" means compounds that are drug precursors
which, following administration to a patient, release the drug in vivo via some
chemical or physiological process (e.g., a prodrug on being brought to the
physiological pH or through enzyme action is converted to the desired drug form).
As used herein, "solvate" means a molecular or ionic complex of molecules
or ions of solvent with those of solute (for example, one or more compounds of
Formula l-XI, isomers of the compounds of Formula l-XI, and prodrugs of the
compounds of Formula l-XI). Non-limiting examples of useful solvents include
polar, protic solvents such as water and alcohols (for example methanol).
In an alternative embodiment, the treatment composition can further
comprise one or more bile acid sequestrant(s) in coadministration with or in
combination with one or more sterol absorption inhibitors.
Non-limiting examples of suitable bile acid sequestrants include
cholestyramine (a styrene-divinylbenzene copolymer containing quaternary
ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or
QUESTRAN LIGHT® which are available from Bristol-Myers Squibb), colestipol (a
copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane, such as
COLESTID® tablets which are available from Pharmacia), colesevelam
hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-
linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-
trimethylammonium bromide) which are available from Sankyo), water soluble
derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insoluble
quaternized polystyrenes, saponins and mixtures thereof. Other useful bile acid
sequestrants are disclosed in PCT Patent Applications Nos. WO 97/1 1345 and WO
98/57652, and U.S. Patents Nos. 3,692,895 and 5,703,188 which are incorporated
WO 02/058696
PCT/US02/01195
42
herein by reference. Suitable inorganic cholesterol sequestrants include bismuth
salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate
antacids.
The bile acid sequestrant(s) are administered in a therapeutically effective
amount to treat the specified condition, for example in a daily dose preferably
ranging from about 1 to about 50 grams per day, and more preferably about 2 to
about 16 grams per day, given in a single dose or 2-4 divided doses. The exact
dose, however, is determined by the attending clinician and is dependent on such
factors as the potency of the compound administered, the age, weight, condition
and response of the patient.
In yet another alternative embodiment, the treatment composition can further
comprise one or more lipid lowering agents such as, for example, sterol
biosynthesis inhibitors, in coadministration with or in combination with one or more
sterol absorption inhibitors.
Non-limiting lipid lowering agents for use in the treatment compositions of
the present invention include HMG CoA reductase inhibitors such as lovastatin,
pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin and itavastatin.
Preferred HMG CoA reductase inhibitors include lovastatin, atorvastatin and
simvastatin. The most preferred HMG CoA reductase inhibitors are atorvastatin and
simvastatin.
In another preferred embodiment, the treatment composition comprises the
compound of Formula (VIII) in combination with a bile acid sequestrant. In this
embodiment, preferably the bile acid sequestrant is selected from cholestyramine,
colesevelam hydrochloride and colestipol. Preferably, the treatment composition
comprises one or more bile acid sequestrants such as, for example,
cholestyramine, colesevelam hydrochloride and colestipol in combination with a
compound of Formula (VIII)
F
(VIII).
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PCT/US02/01195
In another preferred embodiment, the treatment composition comprises the
compound of Formula (VIII) in combination with another lipid lowering agent. In this
embodiment, preferably the lipid lowering agent comprises one or more HMG CoA
reductase inhibitors. Preferably, the treatment composition comprises one or more
HMG CoA reductase inhibitors such as, for example, lovastatin, atorvastatin and
simvastatin in combination with a compound of Formula (VIII)
Still even more preferred, the treatment composition comprises compound of
formula VIII in combination with atorvastatin and/or simvastatin.
In one embodiment of the invention, the compositions or therapeutic
combinations can further comprise one or more pharmacological or therapeutic
agents or drugs such as cholesterol biosynthesis inhibitors and/or lipid-lowering
agents discussed below.
Also useful with the invention are compositions or therapeutic combinations
that can further comprise at least one (one or more) activators for peroxisome
proliferator-activated receptors (PPAR). The activators act as agonists for the
peroxisome proliferator-activated receptors. Three subtypes of PPAR have been
identified, and these are designated as peroxisome proliferator-activated receptor
alpha (PPARa), peroxisome proliferator-activated receptor gamma (PPARy) and
peroxisome proliferator-activated receptor delta (PPAR5). It should be noted that
PPAR5 is also referred to in the literature as PPARp and as NUC1, and each of
these names refers to the same receptor.
F
(VIII).
WO 02/058696
PCT/US02/01195
44
PPARa regulates the metabolism of lipids. PPARa is activated by fibrates
and a number of medium and long-chain fatty acids, and it is involved in stimulating
P-oxidation of fatty acids. The PPARy receptor subtypes are involved in activating
the program of adipocyte differentiation and are not involved in stimulating
peroxisome proliferation in the liver. PPAR5 has been identified as being useful in
increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO
97/28149.
PPARa activator compounds are useful for, among other things, lowering
triglycerides, moderately lowering LDL levels and increasing HDL levels. Useful
examples of PPARa activators include fibric acid derivatives or fibrates.
Non-limiting examples of suitable fibric acid derivatives ('fibrates") include
clofibrate (such as ethyl 2-(p-chlorophenoxy)-2-methyI-propionate, for example
ATROMID-S® Capsules which are commercially available from Wyeth-Ayerst);
gemfibrozil (such as 5-(2,5-dimethylphenoxy)-2,2-dimethyIpentanoic acid, for
example LOPID® tablets which are commercially available from Parke Davis);
ciprofibrate (CAS. Registry No. 52214-84-3, see U.S. Patent No. 3,948,973 which
is incorporated herein by reference); bezafibrate (C.A.S. Registry No. 41859-67-0,
see U.S. Patent No. 3,781,328 which is incorporated herein by reference);
clinofibrate (C.A.S. Registry No. 30299-08-2, see U.S. Patent No. 3,716,583 which
is incorporated herein by reference); binifibrate (C.A.S. Registry No. 69047-39-8,
see BE 884722 which is incorporated herein by reference); lifibrol (C.A.S. Registry
No. 96609-16-4); fenofibrate (such as TRICOR® micronized fenofibrate (2-[4-(4-
chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1 -methylethyl ester) which is
commercially available from Abbott Laboratories or LIPANTHYL® micronized
fenofibrate which is commercially available from Labortoire Founier, France) and
mixtures thereof. These compounds can be used in a variety of forms, including
but not limited to acid form, salt form, racemates, enantiomers, zwitterions and
tautomers.
Other examples of PPARa activators useful with the practice of the present
invention include suitable fluorophenyl compounds as disclosed in U.S. No.
6,028,109 which is incorporated herein by reference; certain substituted
phenylpropionic compounds as disclosed in WO 00/75103 which is incorporated
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PCT/US02/01195
herein by reference; and PPARa activator compounds as disclosed in WO
98/43081 which is incorporated herein by reference.
Non-limiting examples of suitable PPARy activators include derivatives of
glitazones or thiazolidinediones, such as, troglitazone (such as REZULIN®
troglitazone (-5-[[4-[3 ? 4Hjihydro-6-hydroxy-2,5 t 7,8-tetramethyl-2H-1-benzopyran-2-
yl)methoxy]phenyl] methyl]-2,4-thiazolidinedione) commercially available from
Parke-Davis); rosiglitazone (such as AVANDIA® rosiglitazone maleate (-5-[[4-[2-
(methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione,
(Z)-2-butenedioate) commercially available from SmithKline Beecham) and
pioglitazone (such as ACTOS™ pioglitazone hydrochloride (5-[[4-[2-(5-ethyl-2-
pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride)
commercially available from Takeda Pharmaceuticals). Other useful
thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL 49653 as
disclosed in WO 98/05331 which is incorporated herein by reference; PPARy
activator compounds disclosed in WO 00/76488 which is incorporated herein by
reference; and PPARy activator compounds disclosed in U.S. Patent No. 5,994,554
which is incorporated herein by reference.
Other useful PPARy activator compounds include certain acetylphenols as
disclosed in U.S. Patent No. 5,859,051 which is incorporated herein by reference;
certain quinoline phenyl compounds as disclosed in WO 99/20275 which is
incorporated herein by reference; aryl compounds as disclosed by WO 99/38845
which is incorporated herein by reference; certain 1 ,4-disubstituted phenyl
compounds as disclosed in WO 00/63161; certain aryl compounds as disclosed in
WO 01/00579 which is incorporated herein by reference; benzoic acid compounds
as disclosed in WO 01/12612 and WO 01/12187 which are incorporated herein by
reference; and substituted 4-hydroxy-phenylalconic acid compounds as disclosed
in WO 97/31907 which is incorporated herein by reference.
PPAR5 compounds are useful for, among other things, lowering triglyceride
levels or raising HDL levels. Non-limiting examples of PPAR6 activators include
suitable thiazole and oxazole derivates, such as C.A.S. Registry No. 317318-32-4,
as disclosed in WO 01/00603 which is incorporated herein by reference); certain
fluoro, chloro orthio phenoxy phenylacetic acids as disclosed in WO 97/28149
which is incorporated herein by reference; suitable non-fi-oxidizable fatty acid
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PCT/US02/01195
analogues as disclosed in U.S. Patent No. 5,093,365 which is incorporated herein
by reference; and PPAR5 compounds as disclosed in WO 99/04815 which is
incorporated herein by reference.
Moreover, compounds that have multiple functionality for activating various
combinations of PPARa, PPARy and PPAR5 are also useful with the practice of the
invention. Non-limiting examples include certain substituted aryl compounds as
disclosed in U.S. Patent No. 6,248,781; WO 00/23416; WO 00/23415; WO
00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are
incorporated herein by reference, are described as being useful PPARa and/or
PPARy activator compounds. Other non-limiting examples of useful PPARa and/or
PPARy activator compounds include activator compounds as disclosed in WO
97/25042 which is incorporated herein by reference; activator compounds as
disclosed in WO 00/63190 which is incorporated herein by reference; activator
compounds as disclosed in WO 01/21181 which is incorporated herein by
reference; biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is
incorporated herein by reference; compounds as disclosed in WO 00/63196 and
WO 00/63209 which are incorporated herein by reference; substituted 5-aryl-2,4-
thiazolidinediones compounds as disclosed in U.S. Patent No. 6,008,237 which is
incorporated herein by reference; arylthiazolidinedione and aryloxazolidinedione
compounds as disclosed in WO 00/78312 and WO 00/78313G which are
incorporated herein by reference; GW2331 or (2-(4-[difluorophenyl]-
1heptylureido)ethyl]phenoxy)-2-methylbutyric compounds as disclosed in WO
98/05331 which is incorporated herein by reference; aryl compounds as disclosed
in U.S. Patent No. 6,166,049 which is incorporated herein by reference; oxazole
compounds as disclosed in WO 01/17994 which is incorporated herein by
reference; and dithiolane compounds as disclosed in WO 01/25225 and WO
01/25226 which are incorporated herein by reference.
Other useful PPAR activator compounds include substituted
benzylthiazolidine-2,4-dione compounds as disclosed in WO 01/14349, WO
01/14350 and WO/01/04351 which are incorporated herein by reference;
mercaptocarboxylic compounds as disclosed in WO 00/50392 which is
incorporated herein by reference; ascofuranone compounds as disclosed in WO
00/53563 which is incorporated herein by reference; carboxylic compounds as
WO 02/058696 PCT/US02/0 1 1 95
47
disclosed in WO 99/46232 which is incorporated herein by reference; compounds
as disclosed in WO 99/12534 which is incorporated herein by reference; benzene
compounds as disclosed in WO 99/15520 which is incorporated herein by
reference; o-anisamide compounds as disclosed in WO 01/21578 which is
incorporated herein by reference; and PPAR activator compounds as disclosed in
WO 01/40192 which is incorporated herein by reference.
The peroxisome proliferator-activated receptor(s) activator(s) are
administered in a therapeutically effective amount to treat the specified condition,
for example in a daily dose preferably ranging from about 50 to about 3000 mg per
day, and more preferably about 50 to about 2000 mg per day, given in a single
dose or 2-4 divided doses. The exact dose, however, is determined by the
attending clinician and is dependent on such factors as the potency of the
compound administered, the age, weight, condition and response of the patient.
In an alternative embodiment, the compositions or therapeutic combinations
of the invention can further comprise one or more ileal bile acid transport ("IBAT)
inhibitors (or apical sodium co-dependent bile acid transport ("ASBT") inhibitors)
coadministered with or in combination with the sterol absorption inhibitor(s)
discussed above. The IBAT inhibitors can inhibit bile acid transport to reduce LDL
cholesterol levels. Non-limiting examples of suitable IBAT inhibitors include
benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-
benzothiepine 1,1-dioxide structure such as are disclosed in PCT Patent
Application WO 00/38727 which is incorporated herein by reference.
Generally, a total daily dosage of IBAT inhibitor(s) can range from about
0.01 to about 1000 mg/day, and preferably about 0.1 to about 50 mg/day in single
or 2-4 divided doses.
In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise nicotinic acid (niacin) and/or
derivatives thereof coadministered with or in combination with the sterol absorption
inhibitor(s) discussed above.
As used herein, "nicotinic acid derivative" means a compound comprising a
pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including
acid forms, salts, esters, zwitterions and tautomers, where available. Examples of
nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-methyl
WO 02/058696 PCT7US02/01 195
48
pyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and its derivatives inhibit hepatic
production of VLDL and its metabolite LDL and increases HDL and apo A-1 levels.
An example of a suitable nicotinic acid product is N IAS PAN® (niacin extended-
release tablets) which are available from Kos.
Generally, a total daily dosage of nicotinic acid or a derivative thereof can
range from about 500 to about 10,000 mg/day, preferably about 1000 to about
8000 mg/day, and more preferably about 3000 to about 6000 mg/day in single or
divided doses.
In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise one or more
AcylCoArCholesterol O-acyltransferase ("ACAT") Inhibitors, which can reduce LDL
and VLDL levels, coadministered with or in combination with the sterol absorption
inhibitor(s) discussed above. ACAT is an enzyme responsible for esterifying
excess intracellular cholesterol and may reduce the synthesis of VLDL, which is a
product of cholesterol esterification, and overproduction of apo B-100-containing
lipoproteins.
Non-limiting examples of useful ACAT inhibitors include avasimibe ([[2,4,6-
tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-methylethyl)phenyl ester,
formerly known as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 (A/-(2,4-
difluorophenyl)-W-[[4-(2,2-dimethylpropyl)phenyl]methyl]-A/-heptylurea). See P.
Chang et al., "Current, New and Future Treatments in Dyslipidaemia and
Atherosclerosis", Drugs 2000 Jul;60(1 ); 55-93, which is incorporated by reference
herein.
Generally, a total daily dosage of ACAT inhibitors ) can range from about 0.1
to about 1000 mg/day in single or 2-4 divided doses.
In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise one or more Cholesteryl Ester
Transfer Protein ("CETP") Inhibitors coadministered with or in combination with the
sterol absorption inhibitor(s) discussed above. CETP is responsible for the
exchange or transfer of cholesteryl ester carrying HDL and triglycerides in VLDL.
Non-limiting examples of suitable CETP inhibitors are disclosed in PCT
Patent Application No. WO 00/38721 and U.S. Patent No. 6,147,090, which are
incorporated herein by reference. Pancreatic cholesteryl ester hydrolase (pCEH)
WO 02/058696
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PCT/US02/01195
inhibitors such as WAY-121898 also can be coadministered with or in combination
with the peroxisome prol iterator-activated receptor(s) activator and sterol
absorption inhibitor(s) discussed above.
Generally, a total daily dosage of CETP inhibitor(s) can range from about
5 0.01 to about 1000 mg/day, and preferably about 0.5 to about 20 mg/kg body
weight/day in single or divided doses.
In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise probucol or derivatives thereof
(such as AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121,319
10 and 6,147,250), which can reduce LDL levels, coadministered with or in
combination with the sterol absorption inhibitor(s) discussed above.
Generally, a total daily dosage of probucol or derivatives thereof can range
from about 10 to about 2000 mg/day, and preferably about 500 to about 1500
mg/day in single or 2-4 divided doses.
15 In another alternative embodiment, the compositions or treatments of the
invention can further comprise low-density lipoprotein (LDL) receptor activators,
coadministered with or in combination with the sterol absorption inhibitor(s)
discussed above. Non-limiting examples of suitable LDL-receptor activators
include HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates
20 LDL receptor activity. See M. Huettinger et al., "Hypolipidemic activity of HOE-402
is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb.
1993; 13:1005-12.
Generally, a total daily dosage of LDL receptor activator(s) can range from
about 1 to about 1000 mg/day in single or 2-4 divided doses.
25 In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise fish oil, which contains Omega 3
fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels,
coadministered with or in combination with sterol absorption inhibitor(s) discussed
above. Generally, a total daily dosage of fish oil or Omega 3 fatty acids can range
30 from about 1 to about 30 grams per day in single or 2-4 divided doses.
In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise natural water soluble fibers,
such as psyllium, guar, oat and pectin, which can reduce cholesterol levels,
WO 02/058696 PCT/US02/01 195
50
coadministered with or in combination with the sterol absorption inhibitor(s)
discussed above. Generally, a total daily dosage of natural water soluble fibers can
range from about 0.1 to about 10 grams per day in single or 2-4 divided doses.
In another alternative embodiment, the compositions or therapeutic
5 corr: , ... tions of the invention can further comprise plant sterols, plant stanols
and/or fatty acid esters of plant stanols, such as sitostanol ester used in
BENECOL® margarine, which can reduce cholesterol levels, coadministered with
or in combination with the sterol absorption inhibitor(s) discussed above.
Generally, a total daily dosage of plant sterols, plant stanols and/or fatty acid esters
10 of plant stanols can range from about 0.5 to about 20 grams per day in single or 2-4
divided doses.
In another alternative embodiment, the compositions or therapeutic
combinations of the invention can further comprise antioxidants, such as probucol,
tocopherol, ascorbic acid, p-carotene and selenium, or vitamins such as vitamin B 6
15 or vitamin B 12 , coadministered with or in combination with the sterol absorption
inhibitor(s) discussed above. Generally, a total daily dosage of antioxidants or
vitamins can range from about 0.05 to about 10 grams per day in single or 2-4
divided doses.
In another alternative embodiment, the compositions or therapeutic
20 combinations of the invention can further comprise monocyte and macrophage
inhibitors such as polyunsaturated fatty acids (PUFA), thyroid hormones including
throxine analogues such as CGS-26214 (a thyroxine compound with a fluorinated
ring), gene therapy and use of recombinant proteins such as recombinant apo E,
coadministered with or in combination with the sterol absorption inhibitor(s)
25 discussed above. Generally, a total daily dosage of these agents can range from
about 0.01 to about 1000 mg/day in single or 2-4 divided doses.
Also useful with the invention are compositions or therapeutic combinations
which further comprise hormone replacement agents and compositions. Useful
hormone agents and compositions for hormone replacement therapy of the present
30 invention include androgens, estrogens, progestins, their pharmaceutically
acceptable salts and derivatives thereof. Combinations of these agents and
compositions are also useful.
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PCT/US02/01195
The dosage of androgen and estrogen combinations vary, desirably from
about 1 mg to about 4 mg androgen and from about 1 mg to about 3 mg estrogen.
Examples include, but are not limited to, androgen and estrogen combinations such
as the combination of esterified estrogens (sodium estrone sulfate and sodium
equilin sulfate) and methyltestosterone (17-hydroxy-17-methyl-, (17B)- androst-4-
en-3-one) available from Solvay Pharmaceuticals, Inc., Marietta, GA, under the
tradename Estratest.
Estrogens and estrogen combinations may vary in dosage from about 0.01
mg up to 8 mg, desirably from about 0.3 mg to about 3.0 mg. Examples of useful
estrogens and estrogen combinations include:
(a) the blend of nine (9) synthetic estrogenic substances including
sodium estrone sulfate, sodium equilin sulfate, sodium 17 a -dihydroequilin sulfate,
sodium 17 a -estradiol sulfate, sodium 17 p -dihydroequilin sulfate, sodium 17 a -
dihydroequilenin sulfate, sodium 17 p -dihydroequilenin sulfate, sodium equilenin
sulfate and sodium 17 p -estradiol sulfate; available from Duramed
Pharmaceuticals, Inc., Cincinnati, OH, under the tradename Cenestin;
(b) ethinyl estradiol (19-noM 7 a -pregna-1 ,3,5(1 0)-trien-20-yne-3,17-diol;
available by Schering Plough Corporation, Kenilworth, NJ, under the tradename
Estinyl;
(c) esterified estrogen combinations such as sodium estrone sulfate and
sodium equilin sulfate; available from Solvay under the tradename Estratab and
from Monarch Pharmaceuticals, Bristol, TN, under the tradename Menest;
(d) estropipate (piperazine estra-1 ,3,5(1 0)-trien-17-one, 3-(sulfooxy)-
estrone sulfate); available from Pharmacia & Upjohn, Peapack, NJ, under the
tradename Ogen and from Women First Health Care, Inc., San Diego, CA, under
the tradename Ortho-Est; and
(e) conjugated estrogens (17 a-dihydroequilin, 17 a-estradiol, and 17 p-
dihydroequilin); available from Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA,
under the tradename Premarin.
Progestins and estrogens may also be administered with a variety of
dosages, generally from about 0.05 to about 2.0 mg progestin and about 0.001 mg
to about 2 mg estrogen, desirably from about 0.1 mg to about 1 mg progestin and
WO 02/058696 PCI7US02/01 195
52
about 0.01 mg to about 0.5 mg estrogen. Examples of progestin and estrogen
combinations that may vary in dosage and regimen include:
(a) the combination of estradiol (estra-1 , 3, 5 (10)-triene-3, 17 p-diol
hemihydrate) and norethindrone (17 p-acetoxy-19-nor-17 a-pregn-4-en-20-yn-3-
5 one); which is available from Pharmacia & Upjohn, Peapack, NJ, under the
tradename Activella;
(b) the combination of levonorgestrel (d(-)-13 p-ethyl-17 a-ethinyl-17 p-
hydroxygon- 4-en-3-one) and ethinyl estradial; available from Wyeth-Ayerst under
the tradename Alesse, from Watson Laboratories, Inc., Corona, CA, under the
10 tradenames Levora and Trivora, Monarch Pharmaceuticals, under the tradename
Nordette, and from Wyeth-Ayerst under the tradename Triphasil;
(c) the combination of ethynodiol diacetate (19-nor-17 a-pregn-4-en-20-
yne-3 p, 17-diol diacetate) and ethinyl estradiol; available from G.D. Searle & Co.,
Chicago, IL, under the tradename Demulen and from Watson under the tradename
15 Zovia;
(d) the combination of desogestrel (13-ethyl-1 1- methylene-18,19-dinor-
17 a-pregn- 4-en- 20-yn-17-ol) and ethinyl estradiol; available from Organon under
the tradenames Desogen and Mircette, and from Ortho-McNeil Pharmaceutical,
Raritan, NJ, under the tradename Ortho-Cept;
20 (e) the combination of norethindrone and ethinyl estradiol; available from
Parke-Davis, Morris Plains, NJ, under the tradenames Estrostep and femhrt, from
Watson under the tradenames Microgestin, Necon, and Tri-Norinyl, from Ortho-
McNeil under the tradenames Modicon and Ortho-Novum, and from Warner
Chilcott Laboratories, Rockaway, NJ, under the tradename Ovcon;
25 (f) the combination of norgestrel ( (±)-13-ethyl-17-hydroxy-18, 19-dinor-
17 a-preg-4-en-20-yn-3-one) and ethinyl estradiol; available from Wyeth-Ayerst
under the tradenames Ovral and Lo/Ovral, and from Watson under the tradenames
Ogestrel and Low-Ogestrel;
(g) the combination of norethindrone, ethinyl estradiol, and mestranol (3-
30 methoxy-19-nor-17 a-pregna-1 ,3,5(1 0)-trien-20-yn-17-ol); available from Watson
under the tradenames Brevicon and Norinyl;
(h) the combination of 17 p-estradiol (estra-1, 3,5(1 0)-triene-3, 17 p-diol)
and micronized norgestimate (17 a-17-(Acetyloxyl)-13-ethyl-18,19-dinorpregn-4-en-
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20-yn-3-one3-oxime); available from Ortho-McNeil under the tradename Ortho-
Prefest;
(i) the combination of norgestimate (18,19-dinor-17-pregn-4-en-20-yn-3-
one, 17-(acetyloxy)-13-ethyl-,oxime, (17(aH + W a nd ethinyl estradiol; available
from Ortho-McNeil under the tradenames Ortho Cyclen and Ortho Tri-Cyclen; and
(j) the combination of conjugated estrogens (sodium estrone sulfate and
sodium equilin sulfate) and medroxyprogesterone acetate (20-dione, 17-
(acetyloxy)-6-methyl-, (6(a))- pregn-4-ene-3); available from Wyeth-Ayerst under
the tradenames Premphase and Prempro.
In general, a dosage of progestins may vary from about .05 mg to about 10
mg or up to about 200 mg if microsized progesterone is administered. Examples of
progestins include norethindrone; available from ESI Lederle, Inc., Philadelphia,
PA, under the tradename Aygestin, from Ortho-McNeil under the tradename
Micronor, and from Watson under the tradename Nor-QD; norgestrel; available
from Wyeth-Ayerst under the tradename Ovrette; micronized progesterone (pregn-
4-ene-3, 20-dione); available from Solvay under the tradename Prometrium; and
medroxyprogesterone acetate; available from Pharmacia & Upjohn under the
tradename Provera.
The compositions, therapeutic combinations or methods of the invention can
further comprise one or more obesity control medications. Useful obesity control
medications include, but are not limited to, drugs that reduce energy intake or
suppress appetite, drugs that increase energy expenditure and nutrient-partitioning
agents. Suitable obesity control medications include, but are not limited to,
noradrenergic agents (such as diethylpropion, mazindol, phenylpropanolamine,
phentermine, phendimetrazine, phendamine tartrate, methamphetamine,
phendimetrazine and tartrate); serotonergic agents (such as sibutramine,
fenfluramine, dexfenfluramine, fluoxetine, fluvoxamine and paroxtine); thermogenic
agents (such as ephedrine, caffeine, theophylline, and selective (33-adrenergic
agonists); alpha-blocking agents; kainite or AMPA receptor antagonists; leptin-
lipolysis stimulated receptors; phosphodiesterase enzyme inhibitors; compounds
having nucleotide sequences of the mahogany gene; fibroblast growth factor-10
polypeptides; monoamine oxidase inhibitors (such as befloxatone, moclobemide,
brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine,
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sercloremine, bazinaprine, lazabemide, milacemide and caroxazone); compounds
for increasing lipid metabolism (such as evodiamine compounds); and lipase
inhibitors (such as orlistat). Generally, a total dosage of the above-described
obesity control medications can range from 1 to 3 t 000 mg/day, desirably from about
1 to 1 ,000 mg/day and more desirably from about 1 to 200 mg/day in single or 2-4
divided doses.
The compositions, therapeutic combinations or methods of the invention can
further comprise one or more blood modifiers which are chemically different from
the substituted azetidinone and substituted p-Iactarn compounds discussed above.
Useful blood modifiers include but are not limited to anti-coagulants (argatroban,
bivalirudin, dalteparin sodium, desirudin, dicumarol, lyapolate sodium, nafamostat
mesylate, phenprocoumon, tinzaparin sodium, warfarin sodium); antithrombotic
(anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid
sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium, fluretofen,
ifetroban, ifetroban sodium, lamifiban, lotrafiban hydrochloride, napsagatran,
orbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel,
abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifiban acetate,
fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal
antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, clopidogrel bisuffate,
epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen,
naproxen, sulindae, idomethacin, mefenamate, droxicam, diclofenac,
sulfinpyrazone, piroxicam, dipyridamole); platelet aggregation inhibitors (acadesine,
beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine, lotrafiban
hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban,
xemilofiban); hemorrheologic agents (pentoxifylline); lipoprotein associated
coagulation inhibitors; Factor Vila inhibitors (4H-31-benzoxazin-4-ones, 4H-3.1-
benzoxazin-4-thiones, quinazolin-4-ones, quinazolin-4-thiones, benzothiazin-4-
ones, imidazolyl-boronic acid-derived peptide analogues TFPI-derived peptides,
naphthalene-2-sulfonic acid {1 -[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-
(S)-yi} amide trifluoroacetate, dibenzofuran-2-sulfonic acid {1-[3-(aminomethyl>-
benzyl]-5-oxo-pyrrolidin-3-yl}-amide, tolulene-4-sulfonic acid {1-[3-
(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl}-amide trifluoroacetate, 3,4-
dihydro-1 H-isoquinoline-2-sulfonic acid {1 -[3-(aminoiminomethyl)-benzyl]-2-oxo-
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pyrrolin-3-(S)-yl}-amide trifluoroacetate); Factor Xa inhibitors (disubstituted
pyrazolines, disubstituted triazolines, substituted n-[(aminoiminomethyI)phenyl]
propylamides, substituted n-[(aminomethyl)phenyl] propylamides, tissue factor
pathway inhibitor (TFPI), low molecular weight heparins, heparinoids,
benzimidazolines, benzoxazolinones, benzopiperazinones, indanones, dibasic
(amidinoaryl) propanoic afeid derivatives, amidinophenyl-pyrrolidines,
amidinophenyl-pyrrolines/amidinophenyl-isoxazolidines, amidinoindoles,
amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidic Factor Xa
inhibitors). -\
The compositions, therapeutic combinations or methods of the invention can
further comprise one or more cardiovascular agents which are chemically different
from the substituted azetidinone and substituted p-lactam compounds (such as
compounds l-XI above) discussed above. Useful cardiovascular agents include but
are not limited to calcium channel blockers (clentiazem maleate, amlodipine
besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine
hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride, fostedil);
adrenergic blockers (fenspiride hydrochloride, labetalol hydrochloride, proroxan,
alfuzosin hydrochloride, acebutolol, acebutolol hydrochloride, alprenolol
hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol
hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol
hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol
hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride,
levobetaxolol hydrochloride, levobunolol hydrochloride, metalol hydrochloride,
metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate,
practolol, propranolol hydrochloride, sotalol hydrochloride, timolol, timolol maleate,
tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate, nebivolol);
adrenergic stimulants; angiotensin converting enzyme (ACE) inhibitors (benazepril
hydrochloride, benazeprilat, captopril, delapril hydrochloride, fosinopril sodium,
libenzapril, moexipril hydrochloride, pentopril, perindopril, quinapril hydrochloride,
quinaprilat, ramipril, spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate,
lisinopril, zofenopril calcium, perindopril erbumine); antihypertensive agents
(althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine
hydrochloride, cyclothiazide, delapril hydrochloride, dilevalol hydrochloride,
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doxazosin mesylate, fosinopril sodium, guanfacine hydrochloride, methyldopa,
metoprolol succinate, moexipril hydrochloride, monatepil maleate, pelanserin
hydrochloride, phenoxybenzamine hydrochloride, prazosin hydrochloride,
primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride,
5 candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine
maleate, bevantolol hydrochloride); angiotensin II receptor antagonists
(candesartan, irbesartan, losartan potassium, candesartan cilexetil, telmisartan);
anti-anginal agents (amlodipine besylate, amlodipine maleate, betaxolol
hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol,
10 cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate,
primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride); coronary
vasodilators (fostedil, azaclorzine hydrochloride, chromonar hydrochloride,
clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl
tetranitrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, mioflazine
15 hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine,
nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate,
prenylamine, propatyl nitrate, terodiline hydrochloride, tolamolol, verapamil);
diuretics (the combination product of hydrochlorothiazide and spironolactone and
the combination product of hydrochlorothiazide and triamterene).
20 The compositions, therapeutic combinations or methods of the invention can
further comprise one or more antidiabetic medications for reducing blood glucose
levels in a human. Useful antidiabetic medications include, but are not limited to,
drugs that reduce energy intake or suppress appetite, drugs that increase energy
expenditure and nutrient-partitioning agents. Suitable antidiabetic medications
25 include, but are not limited to, sulfonylurea (such as acetohexamide,
chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide, glyburide,
glibenclamide, tolazamide, and tolbutamide), meglitinide (such as repaglinide and
nateglinide), biguanide (such as metformin and buformin), alpha-glucosidase
inhibitor (such as acarbose, miglitol, camiglibose, and voglibose), certain peptides
30 (such as amlintide, pramlintide, exendin, and GLP-1 agonistic peptides), and orally
administrate insulin or insulin composition for intestinal delivery thereof.
Generally, a total dosage of the above-described antidiabetic medications can
range from 0.1 to 1,000 mg/day in single or 2-4 divided doses.
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Mixtures of any of the pharmacological or therapeutic agents described
above can be used in the compositions and therapeutic combinations of the
invention.
The treatment compositions of the invention generally additionally comprise
5 a pharmaceutical^ acceptable carrier diluent, excipient or carrier (collectively
referred to herein as carrier materials). Because of their sterol absorption inhibitory
activity, such pharmaceutical compositions possess utility in treating sitosterolemia
and related disorders.
In the treatment compositions used in the methods of the present invention,
10 the active ingredients will typically be administered in admixture with suitable carrier
materials suitably selected with respect to the intended form of administration, i.e.
oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for
constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and- the
like, and consistent with conventional pharmaceutical practices. For example, for
15 oral administration in the form of tablets or capsules, the active drug component
may be combined with any oral non-toxic pharmaceutical^ acceptable inert carrier,
such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium
phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
Moreover, when desired or needed, suitable binders, lubricants, disintegrating
20 agents and coloring\agents may also be incorporated in the mixture. Powders and
tablets may be comprised of from about 5 to about 95 percent inventive
composition.
Suitable binders include starch, gelatin, natural sugars, com sweeteners,
natural and synthetic gums such as acacia, sodium alginate, carboxymethyl-
25 cellulose, polyethylene glycol and waxes. Among the lubricants there may be
mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium
acetate, sodium chloride, and the like. Disintegrants include starch,
methylcellulose, guar gum and the like. Sweetening and flavoring agents and
preservatives may also be included where appropriate. Some of the terms noted
30 above, namely disintegrants, diluents, lubricants, binders and the like, are
discussed in more detail below.
Additionally, the compositions of the present invention may be formulated in
sustained release form to provide the rate controlled release of any one or more of
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the components or active ingredients to optimize the therapeutic effects, i.e. sterol
absorption inhibitory activity and the like. Suitable dosage forms for sustained
release include layered tablets containing layers of varying disintegration rates or
controlled release polymeric matrices impregnated with the active components and
5 shaped in tablet form or capsules containing such impregnated or encapsulated
porous polymeric matrices.
Liquid form preparations include solutions, suspensions and emulsions. As
an example may be mentioned water or water-propylene glycol solutions for
parenteral injections or addition of sweeteners and pacifiers for oral solutions,
10 suspensions and emulsions. Liquid form preparations may also include solutions
for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids
in powder form, which may be in combination with a pharmaceutical^ acceptable
carrier such as inert compressed gas, e.g. nitrogen.
15 For preparing suppositories, a low melting wax such as a mixture of fatty
acid glycerides such as cocoa butter is first melted, and the active ingredient is
dispersed homogeneously therein by stirring or similar mixing. The molten
homogeneous mixture is then poured into convenient sized molds, allowed to cool
and thereby solidify.
20 Also included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for either oral or
parenteral administration. Such liquid forms include solutions, suspensions and
emulsions.
The compounds of the invention may also be deliverable transdermally. The
25 transdermal compositions may take the form of creams, lotions, aerosols and/or
emulsions and can be included in a transdermal patch of the matrix or reservoir
type as are conventional in the art for this purpose.
Preferably the compound is administered orally, intravenously or
subcutaneously.
30 Preferably, the pharmaceutical preparation is in a unit dosage form. In such
form, the preparation is subdivided into suitably sized unit doses containing
appropriate quantities of the active components, e.g., an effective amount to
achieve the desired purpose.
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The pharmaceutical treatment compositions of the present invention can be
administered to a mammal in need of such treatment in a pharmaceutical^ or
therapeutically effective amount to treat sitosterolemia and/or reduce the level of
sterol(s) in the plasma and tissues.
The term "therapeutically effective amount" means that amount of a
therapeutic agent of the composition, such as the bile acid sequestrant(s), sterol
absorption inhibitors ) and other pharmacological or therapeutic agents described
below, that will elicit a biological or medical response of a tissue, system, animal or
mammal that is being sought by the administrator (such as a researcher, doctor or
veterinarian) which includes alleviation of the symptoms of the sitosterolemic
condition or disease being treated and the prevention, slowing or halting of
progression of the sitosterolemic condition, reduction of the concentration of
sterol(s) and/or 5a-stanol(s) in the plasma and/or tissues, and/or preventing or
reducing the risk of the occurrence of a biological or medical event (such as a
coronary event).
As used herein, "combination therapy" or "therapeutic combination" means
the administration of two or more therapeutic agents, such as sterol absorption
inhibitor(s) and bile acid sequestrant(s) or other therapeutic vascular agents, to
prevent or treat sitosterolemia and/or reduce the level of sterol(s) in the plasma and
tissues. As used herein, "vascular" comprises cardiovascular, cerebrovascular and
combinations thereof. Such administration includes coadministration of these
therapeutic agents in a substantially simultaneous manner, such as in a single
tablet or capsule having a fixed ratio of active ingredients or in multiple, separate
capsules for each therapeutic agent. Also, such administration includes use of
each type of therapeutic agent in a sequential manner. In either case, the
treatment using the combination therapy will provide beneficial effects in treating
the sitosterolemic condition and/or reduce the level of sterol(s) in the plasma and
tissues. A potential advantage of the combination therapy disclosed herein may be
a reduction in the required amount of an individual therapeutic compound or the
overall total amount of therapeutic compounds that are effective in treating the
sitosterolemic condition and/or reducing the level of sterol(s) in the plasma and
tissues. Therapeutic agents can be selected to provide a broader range of
complementary effects or complimentary modes of action.
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The daily dose of the sterol absorption inhibitors) preferably ranges from
about 0.1 to about 30 mg/kg of body weight per day, and more preferably about 0.1
to about 1 5 mg/kg. For an average body weight of 70 kg, the dosage level
therefore ranges from about 1 mg to about 1000 mg of sterol absorption inhibitors)
per day, given in a single dose or 2-4 divided doses. The exact dose, however, is
determined by the attending clinician and is dependent on the potency of the
compound administered, the age, weight, condition and response of the patient.
For the pharmaceutical treatment compositions of the present invention in
which the sterol absorption inhibitor(s) is administered concomitantly or in
combination with a bile acid sequestrant, the typical daily dose of the sequestrant
preferably ranges from about 0.1 to about 80 mg/kg of body weight per day
administered in single or divided dosages, usually once or twice a day. For
example, preferably about 10 to about 40 mg per dose is given 1 to 2 times a day,
giving a total daily dose of about 10 to about 80 mg per day. The exact dose of
sterol absorption inhibitor(s) and bile acid sequestrant(s) to be administered is
determined by the attending clinician and is dependent on the potency of the
compound administered, the age, weight, condition and response of the patient.
Where the sterol absorption inhibitors) and bile acid sequestrant(s) are
administered in separate dosages, the number of doses of each component given
per day may not necessarily be the same, e.g., one component may have a greater
duration of activity and will therefore need to be administered less frequently.
For the pharmaceutical treatment compositions of the present invention in
which the sterol absorption inhibitors) is administered concomitantly or in
combination with a lipid lowering agent, the typical daily dose of the lipid lowering
agent preferably ranges from about 0.1 to about 80 mg/kg of body weight per day
administered in single or divided dosages, usually once or twice a day. For
example, for HMG CoA reductase inhibitors, preferably about 10 to about 40 mg
per dose is given 1 to 2 times a day, giving a total daily dose of about 10 to about
80 mg per day. For other lipid lowering agents, preferably about 1 to about 1000
mg per dose is given 1 to 2 times a day, giving a total daily dose ranging from
about 1 mg to about 2000 mg per day. The exact dose of sterol absorption
inhibitor(s) and lipid lowering agent(s) to be administered is determined by the
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attending clinician and is dependent on the potency of the compound administered,
the age, weight, condition and response of the patient.
Where the sterol absorption inhibitor(s) and lipid lowering agent(s) are
administered in separate dosages, the number of doses of each component given
per day may not necessarily be the same, e.g., one component may have a greater
duration of activity and will therefore need to be administered less frequently.
The formulations and pharmaceutical compositions can be prepared using
conventional pharmaceutical^ acceptable and conventional techniques. The
following formulations exemplify some of the dosage forms of this invention. In
each formulation, the term "active compound" designates a substituted azetidinone
compound, a p-lactam compound or a compound of any of Formulae l-XI described
herein above.
EXAMPLE A
Tablets
No. Ingredient mq/tablet mq/tablet
1 Active Compound 100 500
2 Lactose USP 122 113
3 Corn Starch, Food Grade, as a 10% 30 40
paste in Purified Water
4 Corn Starch, Food Grade 45 40
5 Magnesium Stearate 3 7
Total 300 700
Method of Manufacture
Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate the
mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g.,
1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if
necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and
mix for 1-3 minutes. Compress the mixture to appropriate size and weight on a
suitable tablet machine.
EXAMPLE B
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Capsules
Na Ingredient mq/tablet mq/tablet
1 Active Compound 100 500
2 Lactose USP 106 123
3 Corn Starch, Food Grade 40 70
4 Magnesium Stearate NF 4 7
Total 250 700
Method of Manufacture
Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item
No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin
capsules on a suitable encapsulating machine.
EXAMPLE C
Tablets
No.
Inqredient
ma/tablet
1
Active Compound I
10
2
Lactose monohydrate NF
55
3
Microcrystalline cellulose NF
20
4
Povidone (K29-32) USP
4
5
Croscarmellose sodium NF
8
6
Sodium lauryl sulfate
2
7
Magnesium stearate NF
1
Total
100
Method of Manufacture
Mix Item No. 4 with purified water in suitable mixer to form binder solution.
Spray the binder solution and then water over Items 1 , 2, 6 and a portion of Item 5
in a fluidized bed processor to granulate the ingredients. Continue fluidization to
dry the damp granules. Screen the dried granules and blend with Item No. 3 and
the remainder of Item 5. Add Item No. 7 and mix. Compress the mixture to
appropriate size and weight on a suitable tablet machine.
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In the present invention, the above-described tablet can be coadministered
with a tablet capsule, etc. comprising a dosage of another therapeutic agent such
as are described above, for example a bile acid sequestrant as described above.
Representative formulations comprising other lipid lowering agents are well
administered as a single composition, the dosage forms disclosed above for
substituted azetidinone compounds may readily be modified using the knowledge
of one skilled in the art.
The treatment compositions of the present invention can inhibit the intestinal
absorption of sitosterol in an animal model, as shown in the Example below. Thus,
the treatment compositions of the present invention are hypositosterolemic agents
by virtue of their ability to inhibit the intestinal absorption of sitosterol and can be
useful in the treatment and/or prevention of vascular disease, arteriosclerosis,
atherosclerosis and sitosterolemia in mammals, in particular in humans.
In other embodiments, the present invention provides a method of treating
vascular disease, arteriosclerosis and/or atherosclerosis, comprising administering
to a mammal in need of such treatment an effective amount of at least one
treatment composition comprising at least one sterol and/or stanol absorption
inhibitor to reduce plasma or tissue concentration of at least one non-cholesterol
sterol, such as a phytosterol, 5a-stanol and mixtures thereof.
In another embodiment, the present invention provides a method of treating
or preventing sitosterolemia comprising administering to a mammal in need of such
treatment an effective amount of at least one sterol absorption inhibitor or
pharmaceutical^ acceptable salt or solvate thereof or prodrug thereof.
In another embodiment, the present invention provides a therapeutic
combination comprising:
a) a first amount of the compound of Formula (VIII)
known in the art. It is contemplated that where the two active ingredients are
F
(VIII)
and
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b) a second amount of a lipid lowering agent,
wherein the first amount and the second amount taken together in their totality
comprise a therapeutically effective amount for the treatment or prevention of
sitosterolemia in a mammal.
Normal concentrations or levels of sitosterol in the plasma of humans is
generally less than about 0.2 milligrams/deciliter (mg/dl). Homozygous
s'rtosterolemic humans can exhibit sitosterol levels of greater than 0.2 mg/dl,
typically about 7 to about 60 mg/dl or higher. Heterozygous sitosterolemic humans
can exhibit sitosterol levels of greater than 0.2 mg/dl, typically about 0.3 to about 1
mg/dl or higher.
In another embodiment of the invention, the compositions and therapeutic
combinations of the present invention can reduce plasma and/or tissue
concentration of at least one sterol (including but not limited to phytosterols (such
as sitosterol, campesterol, stigmasterol and avenosterol)) and/or at least one stanol
(including but not limited to 5a-stanols (such as cholestanol, 5a-campestanol, 5ct-
sitostanol)), and mixtures thereof, optionally in combination with cholesterol. The
plasma and/or tissue concentration can be reduced by administering to a mammal
in need of such treatment an effective amount of at least one treatment composition
or therapeutic combination comprising at least one sterol absorption inhibitor or at
least one stanol absorption inhibitor described above. The reduction in plasma
and/or tissue concentration of sterols can range from about 1 to about 70 percent,
and preferably about 10 to about 50 percent of the concentration measured prior to
administration of at least one treatment composition or therapeutic combination
comprising at least one sterol and/or stanol absorption inhibitor described above.
Methods of measuring serum total blood cholesterol and total LDL cholesterol are
well known to those skilled in the art and for example include those disclosed in
PCT WO 99/38498 at page 1 1 , incorporated by reference herein. Methods of
determining levels of other sterols in serum are disclosed in H. Gylling et al„
"Serum Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic
Population", J. Lipid Res. 40: 593-600 (1999), incorporated by reference herein.
In an alternative embodiment, the plasma and/or tissue concentration of
sterols can be reduced by administering to a mammal in need of such treatment an
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effective amount of at least one treatment composition comprising at least one
sterol and/or stanol absorption inhibitor and an effective amount of at least one bile
acid sequestrant.
In a further embodiment, the plasma and/or tissue concentration of sterols
5 can be reduced by administering to a mammal in need of such treatment an
effective amount of at least one treatment composition comprising at least one
sterol and/or stanol absorption inhibitor and an effective amount of at least one
other lipid lowering agent.
Reducing the plasma or tissue concentration of non-cholesterol sterols, such
10 as phytosterol(s) and/or Sa-stanol(s), in a mammal can be useful in the treatment
and/or prevention of vascular conditions or disease, such as vascular inflammation,
arteriosclerosis, atherosclerosis, hypercholesterolemia and sitosterolemia, and
cardiovascular events, stroke and obesity.
Vascular disease is a term that broadly encompasses all disorders of blood
15 vessels including small and large arteries and veins and blood flow. The most
prevalent form of vascular disease is arteriosclerosis, a condition associated with
the thickening and hardening of the arterial wall. Arteriosclerosis of the large
vessels is referred to as atherosclerosis. Atherosclerosis is the predominant
underlying factor in vascular disorders such as coronary artery disease, aortic
20 aneurysm, arterial disease of the lower extremities and cerebrovascular disease.
The methods of the present invention can be used to prevent or reduce the
risk of an occurrence of a fatal or non-fatal cardiovascular event in patients having
no history of clinically evident coronary heart disease prior to the initial
administration of the compounds and treatments of the present invention, as well
25 as patients having a history of clinically evident coronary heart disease. The
phrase "cardiovascular event" includes but is not limited to fatal and non-fatal acute
major coronary events, coronary revascularization procedures, peripheral vascular
disease, stable angina and cerebrovascular insufficiency such as stroke.
The phrase "acute major coronary event" includes fatal myocardial infarction,
30 witnessed and unwitnessed cardiac death and sudden death occurring from 1 hour
up to 24 hours after collapse, non-fatal myocardial infarction including definite acute
Q-wave myocardial infarction; non-Q-wave myocardial infarction, and silent
subclinical (remote) myocardial infarction, and unstable angina pectoris. As used
I.
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herein, "myocardial infarction" includes both Q-wave and non-Q-wave myocardial
infarction and silent subclinical (remote) myocardial infarction.
In another embodiment, the present invention provides a method of
preventing or reducing risk of a cardiovascular event comprising administering to a
5 mammal an effective amount of at least one treatment composition comprising at
least one sterol and/or stanol absorption inhibitor to reduce plasma or tissue
concentration of at least one non-cholesterol sterol, such as phytosterols, at least
one stanol, such as 5a-stanols, and mixtures thereof.
In another embodiment, the present invention provides a method of
10 preventing or reducing risk of a cardiovascular event comprising administering an
effective amount of at least one treatment composition comprising at least one
sterol absorption inhibitor to reduce plasma or tissue concentration of at least one
non-cholesterol sterol, such as phytosterols, at least one stanol, such as 5a-
stanols, and mixtures thereof to a mammal having no history of clinically evident
is coronary heart disease prior to the initial administration.
Illustrating the invention are the following examples which, however, are not
to be considered as limiting the invention the their details. Unless indicated
otherwise, all parts and percentages in the following examples, as well as
throughout the specification, are by weight.
20
EXAMPLE 1
In Vivo Evaluation In Mice
In vivo activity of compound VIII in mice was determined by the following
procedure:
25 Male ApoE knockout mice, age 6wks, were received from Jackson
Laboratory along with age-matched C57BLAJ. The mice were housed 5 per cage,
normal light cycle, normal diet. Twenty-six mice of each variety were weighed and
housed, 1 per cage, in suspended wire cages with normal light cycle, normal diet.
After three days, the mice were reweighed. Based on body weight, the mice were
30 divided into 5 groups for each type of treatment:
Control (com oil) and Compositions including Compound VIII at 0.3, 1, 3, and 10
mg/kg of body weight per day.
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Preparation of Compositions including Compound VIII based on 22g
average mouse body weight:
Dosage of Compound VIII (mg/ml/day) Compound VIII (ml) + corn oil (ml)
10mg/kg/day in 0.1 ml com oil 2.2mg/ml* 10ml=22 mg in 10ml corn oil
The mice were gavaged using a feeding needle 30 min before receiving 14 C-
cholesterol (NEN, NEC 018) and 3 H-sitosterol (NEN, CUS 030T). The radioactive
dose was prepared from:
114 pL 3 H-sitosterol stock (1 pCi/pL in ethanol);
1.425 mL 14 C-cholesterol stock (40 pCi/mL in ethanol);
5.7 mg cholesterol, Sigma C 8667;
5.7 mg G-sitosteroi, Sigma, S 1270;
The ethanol was removed under N 2:
5.7 ml of corn oil was added, and the mixture was warmed to 60°C; and
shaken for 1 hr.
Each 0.1ml dose contained 2 pCi 3 H-sitosterol, 0.1 mg cold (non radioactive)
sitosterol; 1 pCi 14 C-cholesterol, and 0.1 mg cold (non radioactive) cholesterol.
Radioactive content was verified: 5 X 10 pi counted in Beckman LSC (liquid
simulation counter). Tritiated sitosterol was used as an "unabsorbable" marker to
compare to the absorption of [ 14 C]-cholesterol in a mouse fecal isotope ratio
cholesterol absorption model.
On the 4 th , 5 th , and 6 th days, feces were collected and stored at -20°C in
vials just before dosing with Control or Compound VIII late in the day. Termination
of the experiment on the 7 th day involved sacrifice by exsanguination, removal and
weighing of the liver. 3 X -250 mg samples of liver were put in vials. The liver
samples were digested with 1ml of 1N NaOH at 60° overnight, neutralized with
0.1ml 12N HCI and counted for 14 C and 3 H. The blood samples were allowed to
clot at room temp for 1 hr, then centrifuged at 1000G for 15 min. The serum was
analyzed for total cholesterol (see Wako CM; see Allain CC, Poon LS, Chan CSG,
Richmond W, Fu PC.Enzymatic Determination of Total Serum Cholesterol. Clin.
Chem. 1974; 20:470-475, which is incorporated by reference herein) and
3mg/kg : _
1mg/kg :
0.3mg/kg :
3 ml of 10mg/kg + 7 ml com oil;
3 ml of 3mg/kg + 6 ml com oil;
2ml of 1mg/kg + 4.67 ml corn oil.
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radioactivity (2 X 50pL). Fecal samples were analyzed for radioactivity by
combustion in a Packard Oxidizer followed by Beckman LSC.
In this experiment, Wild type mice (C57BL/6J) and mice deficient in
apoprotein E (Apo E KO) were found to absorb from 0.15-0.38% of the original [ 3 H]-
5 sitosterol dose administered into their livers. When Compound VIII was given, it
was found to dose dependency inhibit the absorption and hepatic accumulation of
sitosterol as shown in Table 1 below.
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Table 1.
Effect of Compound VIII on Sitosterol Absorption in Mice
Mouse
strain
Treatment
% of administered dose absorbed of pH]-
sitosterol in liver (total animal liver)
average
±sem
P =
C57BL/6J
Control
0 1479
+n o^T7
Compound VIII
0.3mg/kg
o men
ZU.U IH-O
Compound VIII
1mg/kg
U.UJOO
XU.U I I o
^.U40 )
Compound VIII
3mg/kg
0.0489
±0.0067
(.024)
Compound VIII
1 0mg/kg
0.0552
±0.0151
(.040)
ApoE KO
Control
n ^77^
U.O/ 1 o
ZU.UDZD
Compound VIII
0.3mg/kg
U. 1 ODO
ZU.Uii*tO
U.U1 o
Compound VIII
1mg/kg
0.1019
±0.0225
0 0019
Compound VIII
3mg/kg
0.0772
±0.0050
0.0023
Compound VIII
10mg/kg
0.0780
±0.0179
0.0017
N = 4-6 mice per treatment
sem= standard error of mean
p= probability
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EXAMPLE 2
In Vivo Evaluation In Humans
In a randomized multicenter, double-blind, placebo-controlled, 8-week trial,
37 human patients previously diagnosed with homozygous sitosterolemia were
randomized to receive Compound VIII (n=30) or placebo (n=7):
Treatment A- Compound VIII given orally as 1 dose (10 mg) per day,
Treatment B - Placebo (matching image of Compound VIII 10 mg)
given orally as 1 dose per day, every morning for 8 consecutive weeks.
During the trial, subjects were instructed to maintain (as a minimum) a
National Cholesterol Education Program (NCEP) Step 1 diet
Patients were instructed to maintain a diary of food intake and monitored
prior to randomization, at baseline and during therapy. Results of the central diet
analysis for each subject were reported as a RISCC score (Ratio of Ingested
Saturated fat and Cholesterol to Calories) and as dietary components. RISCC
scores indicate the potential for a diet to influence plasma lipid levels. A score
ranging from 14 to 20 correlates with a NCEP step 1 diet.
Lipid/lipoproteins determinations
Low-Density -Lipoprotein-Cholesterol (LDL-C) results were reported as
direct LDL-C (plasma concentration was determined following a standard ultra
centrifugation/precipitation procedure; lipid and lipoprotein analysis, see Manual of
Laboratory Operations: Lipid Research Clinics Program Report. Washington. DC:
US Department of Health, Education, and Welfare publication; 1974. NIH 75-628,
vol 1, which is incorporated by reference herein or beta-quantification) and
calculated LDL-C (plasma concentration; based on Freidewald equation: LDL-C =
Total cholesterol minus (Triglycerides divided by 5) minus High-density -lipoprotein
cholesterol (HDL-C)).
Total cholesterol and Triglycerides were determined enzymatically using a
Hitachi 747 analyzer; see, Steiner PM, Freidel J, Bremner WF, Stein EA:
Standardization of micromethods for plasma cholesterol, triglyceride and HDL-
cholesterol with the Lipid Clinics' methodology [abstract]. J Clin Chem Clin Biochem
1 981 ;1 9:850, which is incorporated by reference herein.
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HDL-C was determined enzymatically after heparin and magnesium
precipitation; see, Steele WB, Koehle DF, Azar MM, Blaszkowski TP. Kuba K,
Dempsey ME: Enzymatic determinations of cholesterol in high density lipoprotein
fractions prepared by precipitation technique. Clin Chew 1976;22:98-101, which is
incorporated by reference herein.
Plasma plant sterols (sitosterol and campesterol) and LDL-C were assessed
at baseline (Day 1 ) and at endpoint (average of Weeks 6 and 8 values). See:
Salen, Gerald; Shore, Virgie; Tint, GS; Forte, T: Shefer, S; Horak, I; Horak, E;
Dayal, B; Nguyen, L; Batta, AK; Lindgren, FT; Kwiterovich, Jr, PO, "Increased
sitosterol absorption, decreased removal and expanded body pools compensate for
reduced cholesterol synthesis in sitosterolemia with xanthomatosis", J Lipid Res,
Vol. 30, pp 1319-30, (1989) and Lutjohann, D; Bjorkhem, I; Beil, UF, and von
Bergmann, K, "Sterol absorption and sterol balance in phytosterolemia evaluated
by deuterium-labeled sterols: effect of sitostanol treatment" J Lipid Res. Vol. 36:(8),
pp 1763-73, (1995), each of which is incorporated by reference herein.
Results:
The mean (S.E.) percent (%) change from Baseline at endpoint in plant sterols
and LDL-C (mean, 95% CI) are shown in Table 1 below:
Table 1
Treatment Sitosterol Campesterol LDL-C
A -21.0% (2.8%) -24.3% (2.9%) -13.6% (-21.7%, -5.5%)
B (control) 4.0% (5.3%) 3.2% (5.5%) 16.7% (31.6%, 64.9%)
The coadministration of 10 mg of Compound VIII was well tolerated and
caused a significant (p< 0.001) reduction in sitosterol and campesterol compared to
placebo.
Preparation of Compound (VIII)
Step 1 ): To a solution of (S)-4-P hen y , - 2 - oxazo, ' c, ' none ( 41 9. 0-25 mol) in
CH2CI2 (200 ml), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and
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triethylamine (84.7 ml, 0.61 mol) and the reaction mixture was cooled to 0°C.
MethyM-(chlorofonriyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2CI2
(375 ml) dropwise over 1 h, and the reaction was allowed to warm to 22°C. After
17 h, water and H2SO4 (2N, 100 ml), was added the layers were separated, and
the organic layer was washed sequentially with NaOH (10%), NaCI (sat'd) and
water. The organic layer was dried over MgS04 and concentrated to obtain a
semicrystalline product.
Step 2): To a solution of TiCl4 (18.2 ml, 0.165 mol) in CH2CI2 (600 ml) at
0°C, was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min, the
product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2CI2 (100 ml).
After 5 min., diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) was added and the
reaction mixture was stirred at 0°C for 1 h, the reaction mixture was cooled to -
20°C, and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added
as a solid. The reaction mixture was stirred vigorously for 4 h at -20°C, then acetic
acid was added as a solution in CH2CI2 dropwise over 15 min, the reaction mixture
was allowed to warm to 0°C, and H2SO4 (2N) was added. The reaction mixture
was stirred an additional 1 h, the layers were separated, washed with water,
separated and the organic layer was dried. The crude product was crystallized
from ethanol/water to obtain the pure intermediate.
Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene
(100 ml) at 50°C, was added N,0-bis(trimethylsilyl)acetamide (BSA) (7.50 ml, 30.3
mmol). After 0.5 h, solid TBAF (0.39 g, 1 .5 mmol) was added and the reaction
mixture stirred at 50°C for an additional 3 h. The reaction mixture was cooled to
22°C, CH3OH (10 ml), was added. The reaction mixture was washed with HCI
(1N), NaHC03 (1N) and NaCI (sat'd.), and the organic layer was dried over
MgS04.
Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH
(3 ml), was added water (1 ml) and UOH H2O (102 mg, 2.4 mmole). The reaction
mixture was stirred at 22°C for 1 h and then additional UOHH2O (54 mg, 1.3
mmole) was added. After a total of 2 h, HCI (1N) and EtOAc was added, the layers
WO 02/058696 PCT/US02/01 195
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were separated, the organic layer was dried and concentrated in vacuo. To a
solution of the resultant product (0.91 g, 2.2 mmol) in CH2CI2 at 22°C, was added .
CICOCOCI (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The solvent was
removed in vacuo.
Step 5): To an efficiently stirred suspension of 4-fluorophenylzinc chloride
(4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1M in THF, 4.4 ml,
4.4 mmol) and ZnCl2 (0.6 g, 4.4 mmol) at 4°C, was added tetrakis(triphenyl-
phosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g,
2.2 mmol) as a solution in THF (2 ml). The reaction was stirred for 1 h at 0°C and
then for 0.5 h at 22°C. HCI (1N, 5 ml) was added and the mixture was extracted
with EtOAc. The organic layer was concentrated to an oil and purified by silica gel
chromatography to obtain 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(RH3-oxo-3-
phenylpropyl)-2-azetidinone:
HRMS calc'd for C24H19F2NO3 = 408.1429, found 408.1411.
Step 6): To the product of Step 5 (0.95 g, 1 .91 mmol) in THF (3 ml), was
added (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2]
oxazaborole (120 mg, 0.43 mmol) and the mixture was cooled to -20°C. After 5
min, borohydride-dimethylsulfide complex (2M in THF, 0.85 ml, 1.7 mmol) was
added dropwise over 0.5 h. After a total of 1 .5 h , CH3OH was added followed by
HCI (1 N) and the reaction mixture was extracted with EtOAc to obtain 1-(4-
fluorophenyl)-3(R)-[3(SH4-fluorophenyl)-3-hydroxypropyl)]-4(S)-[4-
(phenylmethoxy)phenyl]-2-azetidinone (compound 6A-1) as an oil. 1 H in CDCI3 d
H3 = 4.68. J = 2.3 Hz. CI (M + H) 500.
Use of (S)-tetra-hydro-1-methyl-3,3-diphenyl-1 H,3H-pyrroio-[1 ,2-c][1 ,3,2]
oxazaborole gives the corresponding 3(R)-hydroxypropyl azetidinone (compound
6B-1). 1 HinCDCl3dH3 = 4.69. J = 2.3 Hz. CI (M + H) 500.
To a solution of compound 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 ml), was
added 10% Pd/C (0.03 g) and the reaction mixture was stirred under a pressure (60
psi) of H2 gas for 16 h. The reaction mixture was filtered and the solvent was
concentrated to obtain compound 6A. Mp 164-166°C; CI (M + H) 410.
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[ctg 5 = -28.1° (c 3, CH 3 OH) E | ementa | analysis calc'd for C24H21F2NO3: C
70.41; H 5.17; N 3.42; found C 70.25; H 5.19; N 3.54.
Similarly treat compound 6B-1 to obtain compound 6B.
Mp 1 29.5-1 32.5°C; CI (M + H) 410. Elemental analysis calc'd for C24H21F2NO3:
C 70.41; H5.17; N 3.42; found C 70.30; H 5.14; N 3.52.
Step 6' (Alternative): To a solution of the product of Step 5 (0.14 g, 0.3
mmo!) in ethanol (2 ml), was added 10% Pd/C (0.03 g) and the reaction was stirred
under a pressure (60 psi) of H2 gas for 16 h. The reaction mixture was filtered and
the solvent was concentrated to afford a 1:1 mixture of compounds 6A and 6B.
It will be appreciated by those skilled in the art that changes could be made
to the embodiments described above without departing from the broad inventive
concept thereof. It is understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover modifications which
are within the spirit and scope of the invention, as defined by the appended claims.
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Therefore, I claim:
1 . A method of treating or preventing sitosterolemia, comprising
administering to a mammal in need of such treatment an effective amount of at
least one sterol absorption inhibitor, or pharmaceutical^ acceptable salt or solvate
of the least one sterol absorption inhibitor, or prodrug of the at least one sterol
absorption inhibitor or pharmaceutical^ acceptable salt or solvate of the least one
sterol absorption inhibitor, or mixture thereof.
2. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (I):
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (I) or of the isomers thereof, or prodrugs of the compounds
of Formula (I) or of the isomers, salts or solvates thereof, wherein:
Ar 1 is R^-substituted aryl;
Ar 2 is R 4 -substituted aryl;
Ar^ is R^-substituted aryl;
Y and Z are independently selected from the group consisting of -CH2-,
-CH(lower alkyl)- and -C(dilower alkyl)-;
A is -0-, -S-, -S(Oy or -S(0)2-;
R1 is selected from the group consisting of -OR 6 , -0(CO)R 6 , -0(CO)OR 9
and -0(CO)NR6r7 ;
R 2 is selected from the group consisting of hydrogen, lower alkyl and aryl;
or R 1 and R 2 together are =0;
q is 1, 2 or 3;
pis 0, 1,2, 3 or 4;
R 1
Ar 1 -A-Yq-C-Z,
(I)
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R5 is 1-3 substituents independently selected from the group consisting of -
OR6 -0(CO)R 6 , -0(CO)OR 9 , -0(CH2)1-50R 9 , -0(CO)NR6r 7 .nr6r 7
-NR6(CO)R 7 , -NR6(CO)OR9, -NR6(CO)NR 7 r8 -NR6s02-lower alkyl, -NR6SO2-
aryl, -CONR6r 7 -COR6 -S02lMR 6 R 7 S(O)0-2-alkyl, S(O)0-2-aryl,
-O(CH2)l.10-COOR 6 r O(CH2)l.10CONR 6 R 7 , o-halogeno, m-halogeno, o-lower
alkyl, m-lower alkyl, -(lower a!kylene)-COOR 6 , and -CH=CH-COOR 6 ;
R 3 and R 4 are independently 1-3 substituents independently selected from
the group consisting of R 5 , hydrogen, p-lower alkyl, aryl, -NO2, -CF3 and p-
halogeno;
R6, R 7 and R& are independently selected from the group consisting of
hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted lower alkyl.
3. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (II):
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (II) or of the isomers thereof, or prodrugs of the compounds
of Formula (II) or of the isomers, salts or solvates thereof, wherein:
A is selected from the group consisting of R 2 -substituted heterocycloalkyl,
R2-substituted heteroaryl, R 2 -substituted benzofused heterocycloalkyl, and R 2 -
substituted benzofused heteroaryl;
Ar 1 is aryl or R 3 -substituted aryl;
Ar 2 is aryl or R 4 -substituted aryl;
Ar 1 -R 1 -Q.
0'
N
Ar 2
(ID
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Q is a bond or, with the 3-position ring carbon of the azetidinone, forms the
"Rf-(R 6 )a
spiro group v ;b
r1 is selected from the group consisting of
-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q
can also be zero or 1 ;
-(CH2)e-G-(CH2)r. wherein G is -0-, -C(0>, phenylene, -NR 8 - or
-S(0)rj-2-e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6 alkenylene)-; and
-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is
0-5, provided that the sum of f and g is 1-6;
R5 is
-CH-, -C(C r C 6 alkyl)-, -CF-, -C(OH)-, -C(C 6 H 4 -R 9 )-,-N-, or- + NO" ;
R 6 and R 7 are independently selected from the group consisting of -CH2-,
-CH(Ci-C6 alkyl)-, -C(di-(Ci-C6) alkyl), -CH=CH- and -C(C-|-C6 alkyl)=CH-; or R 5
together with an adjacent R 6 , or R 5 together with an adjacent R 7 , form a -CH=CH-
or a -CH=C(Ci-C6 alkyl)- group;
a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided
that when R 6 is -CH=CH- or -C(Ci-C6 alkyl)=CH-, a is 1 ; provided that when R 7 is
-CH=CH- or -C(Ci-C6 alkyl)=CH-, b is 1 ; provided that when a is 2 or 3, the R 6 's
can be the same or different; and provided that when b is 2 or 3, the R 7 's can be
the same or different;
and when Q is a bond, R 1 also can be:
Rio |f 12 Rio R10
-M-Yd-C-Zh-, -X m -(C) S -Y n -(C),-Zp- or -X r (C) v -Y k -S(0)o. 2 -;
R 11 R 13 r11 R 11
M is -O-, -S-, -S(O)- or -S(0)2S
X, Y and Z are independently selected from the group consisting of -CH2-,
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-CH(Ci-C6 alkyl)- and -C(di-(Ci-C6) alky!);
R 10 and R 12 are independently selected from the group consisting of
-OR 14 , -0(CO)R 14 , -0(CO)OR 1 6 and -0(C0)NR1 4 R 1 5;
R 1 1 and R 13 are independently selected from the group consisting of
hydrogen, (C-|-C6)alkyl and aryl; or R 10 and R 1 1 together are =0, or
R 12 and R 1 3 together are =0;
dis 1,2 or 3;
his 0,1,2, 3 or 4;
s is 0 or 1 ; t is 0 or 1 ; m, n and p are independently 0-4; provided that at
least one of s and t is 1 , and the sum of m, n, p, s and t is 1-6; provided that when
p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s
is 1, the sum of m, t and n is 1-5;
v is 0 or 1 ;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
r2 is 1-3 substituents on the ring carbon atoms selected from the group
consisting of hydrogen, (Ci-Cio)alkyl, (C2-Cio)alkenyl, (C2-Cio)alkynyl,
(C3-C6)cycloalkyl, (C3-C6)cycloaIkenyl, R 17 -substituted aryl, R 17 -substituted
benzyl, R 17 -substituted benzyloxy, R 1 ^substituted aryloxy, halogeno, -NR 14 R 15 ,
NR14r1 5(Ci-C6 alkyleneh NR 14 R 15 C(0)(Ci-C6 alkylene)-,-NHC(0)R 1 6 OH,
C1-C6 alkoxy, -OC(0)R 1 6 -COR 14 , hydroxy(Ci-C6)alkyl, ^Ci-C6)alkoxy(Ci-
C6)alkyl, NO2, -S(0)o-2R 16 , -S02NR1 4 R15 and -(C1-C6 alkylene)COORl 4 ;
when R 2 is a substituent on a heterocycloalkyl ring, R 2 is as defined, or is =0
I (CH 2 h. 2
or o' ; and, where R 2 is a substituent on a substitutable ring nitrog<
is hydrogen, (Ci-C6)alkyl, aryl, (Ci-C6)alkoxy, aryloxy, (Ci-C6)alkylcarbonyl,
arylcarbonyl, hydroxy, -(CH2)1-6C0NR 18 R 18 ,
wherein J is -0-, -NH-, -NR18. or .CH2-;
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R 3 and R 4 are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of (Ci-C6)alkyl,
•OR 14 , -0(CO)R 14 , -0(CO)OR 16 , -0(CH2)1-50R 14 -0(CO)NR 14 R 1 5,
_ NR 14 R 15 t .NR1 4 (C0)R15, .NR1 4 (C0)0R 16 , -NR 14 (CO)NR 1 5r19
-NR1 4 S02R 16 , -COOR™, -C0NR 14 R15, -COR 14 , -S02NR1 4 R 15 , S(O)0-2R 16 ,
-0(CH2)1-10-COOR 14 .0(CH2)1-10CONR 14 R 15 , -(C1-C6 alkylene)-COOR 14 ,
-CH=CH-COOR 14 -CF3, -CN, -N02 and halogen;
R8 is hydrogen, (Ci-C6)alkyl, aryl (Ci-C6)alkyl, -C(0)R 14 or-COOR 14 ;
R 9 and R 17 are independently 1-3 groups independently selected from the
group consisting of hydrogen, (Ci-C6)alkyl, (C-|-C6)alkoxy, -COOH, NO2,
-NR 14 R 1 5 OH and halogeno;
R 14 and R 15 are independently selected from the group consisting of
hydrogen, (Ci-C6)alkyl, aryl and aryl-substituted (Ci-C6)alkyl;
R 16 is (Ci-C6)alkyl, aryl or R 1 ^substituted aryl;
R 18 is hydrogen or (Ci-C6)alkyl; and
R 19 is hydrogen, hydroxy or (C-|-C6)alkoxy.
4. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (III):
R
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (III) or of the isomers thereof, or prodrugs of the
compounds of Formula (III) or of the isomers, salts or solvates thereof, wherein:
Ar 1 is aryl, R 10 -substituted aryl or heteroaryl;
Ar 2 is aryl or R 4 -substituted aryl;
Ar 3 is aryl or R 5 -substituted aryl;
(III)
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X and Y are independently selected from the group consisting of -CH2-,
-CH(lower alkyl)- and -C(dilower alkyi)-;
R is -OR 6 , -0(CO)R 6 -0(CO)OR 9 or -0(CO)NR 6 R 7 ;
R1 is hydrogen, lower alkyl or aryl; or R and R^ together are =0;
. :.r1;
r is 0, 1 or 2;
m and n are independently 0, 1 , 2, 3, 4 or 5; provided that the sum of m, n
and q is 1, 2, 3, 4 or 5;
R 4 is 1-5 substituents independently selected from the group consisting of
lower alkyl, -OR 6 , -0(CO)R 6 , -0(CO)OR 9 , -0(CH2)1-50R 6 , -0(CO)NR 6 R 7 ,
-NR 6 R 7 , -NR 6 (CO)R 7 , -NR 6 (CO)OR 9 , -NR 6 (CO)NR 7 R 6 , -NR 6 S02R 9 , -COOR 6 ,
-CONR 6 R 7 -COR 6 , -S02NR 6 R 7 , S(O)0-2R 9 . -0(CH2)1-10-COOR 6 ,
-0(CH2)1-10CONR 6 R7, -(lower alkylene)COOR 6 and -CH=CH-COOR 6 ;
R 5 is 1-5 substituents independently selected from the group consisting of
-OR 6 , -0(CO)R 6 , -0(CO)OR 9 , -0(CH2)1-50R 6 . -0(CO)NR 6 R 7 , -NR 6 R 7 ,
-NR 6 (C0)R 7 , -NR 6 (CO)OR 9 -NR 6 (CO)NR 7 R 6 . -NR 6 S02R 9 , -COOR 6 ,
-CONR 6 R 7 , -COR 6 , -S02NR 6 R 7 , S(O)0-2R 9 . -0(CH2)1-10-COOR 6 ,
-0(CH2)1-10CONR 6 R 7 , -CF3, -CN. -NO2, halogen, -(lower alkylene)COOR 6 and
-CH=CH-COOR 6 ;
R 6 , R 7 and R 6 are independently selected from the group consisting of
hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R 9 is lower alkyl, aryl or aryl-substituted lower alkyl; and
R 16 is 1-5 substituents independently selected from the group consisting of
lower alkyl, -OR 6 , -0(CO)R 6 -0(CO)OR 9 , -0(CH2)1-50R 6 , -0(CO)NR 6 R 7
-NR 6 R 7 , -NR 6 (CO)R 7 , -NR 6 (CO)OR 9 , -NR 6 (CO)NR 7 R 6 , -NR 6 S02R 9 , -COOR 6 ,
-CONR 6 R 7 , -COR 6 , -S02NR 6 R 7 S(O)0-2R 9 . -O(CH2)l-10-COOR 6 .
-0(CH2)1-10CONR 6 R 7 , -CF3, -CN, -NO2 and halogen.
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5. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (IV):
R4
X R-(R 2 )v / R2 °
(R 3 )u-
0 R21
(IV)
or isomers thereof, or pharmaceutically acceptable salts or solvates of the
compounds of Formula (IV) or of the isomers thereof, or prodrugs of the
compounds of Formula (IV) or of the isomers, salts or solvates thereof, wherein:
R1 is
-CH-, -C(lower alkyl)-, -tf-, -fc(OH)-, -fc(C 6 H 5 )-, -fc(C 6 H 4 -Ri5)-.
1 1
-N- or - NO" ;
1
R2 and R3 are independently selected from the group consisting of:
-CH2-. -CH(lower alkyl)-, -C(di-lower alkyl)-, -CH=CH- and -C(lower alkyl)=CH-; or
R1 together with an adjacent R2, or R1 together with an adjacent R3, form a
-CH=CH- or a -CH=C(lower alkyl)- group;
u and v are independently 0, 1 , 2 or 3, provided both are not zero; provided
that when R2 is -CH=CH- or -C(lower alkyl)=CH-, v is 1; provided that when R3 is
-CH=CH- or -C(lower alkyl)=CH-, u is 1 ; provided that when v is 2 or 3, the R2*s can
be the same or different; and provided that when u is 2 or 3, the R3's can be the
same or different;
R4 is selected from B-(CH2)mC(0)-, wherein m is 0, 1, 2, 3, 4 or 5;
B-(CH2)q-, wherein q is 0, 1, 2, 3, 4, 5 or 6;
B-(CH2) e -Z-(CH2)r. wherein Z is -0-, -C(O)-, phenylene, -N(R8>- or
-S(O)0-2-. e is 0, 1 . 2, 3, 4 or 5 and r is 0, 1 , 2, 3, 4 or 5, provided that the
sum of e and r is 0, 1 , 2, 3, 4, 5 or 6;
B-(C2-C6 alkenylene)-;
B-(C4-C6 alkadienylene)-;
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B-(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z is as defined above, and
wherein t is 0, 1 , 2 or 3, provided that the sum of t and the number of carbon
atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1 , 2, 3, 4 or 5
and g is 0, 1 , 2, 3, 4 or 5, provided that the sum of f and g is 1 , 2, 3, 4, 5 or 6;
B-(CH2)t-V-(C2-C6 alkenylene)- or
B-(C2-C6 alkenylene)-V-(CH2)t-, wherein V and t are as defined above,
provided that the sum of t and the number of carbon atoms in the alkenylene
chain is 2, 3, 4, 5 or 6;
B-(CH2) a -Z-(CH2)b-V-(CH2)d-, wherein Z and V are as defined above and
a, b and d are independently 0, 1 , 2, 3, 4, 5 or 6, provided that the sum of a,
b and d is 0, 1, 2, 3, 4, 5 or 6; orT-(CH2) s -, wherein T is cycloalkyl of 3-6
carbon atoms and s is 0, 1 , 2, 3, 4, 5 or 6; or
Rl and R4 together form the group B-CH=C- ;
B is selected from indanyl, indenyl, naphthyl, tetrahydronaphthyl, heteroaryl
or W-substituted heteroaryl, wherein heteroaryl is selected from the group
consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl,
pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the
N-oxides thereof, or
W is 1 to 3 substituents independently selected from the group consisting
of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl. alkoxyalkoxy,
alkoxycarbonylalkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, lower
alkyl lower alkanedioyl. allyloxy, -CF3, -OCF3. benzyl, Rz-benzyl, benzyloxy,
R7-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, N02,-N(R8)(R9).
N(R8)(R9Hower alkylene-, N(R8)(Rg)-lower alkylenyloxy-, OH, halogeno, -CN, -N3,
-NHC(O)ORi 0 . -NHC(O)Ri0. R11O2SNH-, (Rn02S)2N-, -S(0)2NH 2 ,
-S(0)o-2R8. tert-butyldimethyl-silyloxymethyl, -C(0)Ri2, -COOR19, -CON(R8)(R9),
-CH=CHC(0)Ri2, -lower alkylene-C(0)Ri2, RioC(0)(lower alkylenyloxy)-,
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/ N>
- CH 2 - N R13
N(R8)(R9)C(0)(lower alkylenyloxy)- and N — ' for substitution on ring
carbon atoms,
and the substituents on the substituted heteroaryl ring nitrogen atoms, when
present, are selected from the group consisting of lower alkyl, lower alkoxy,
-C(0)ORio. -C(0)R<io, OH, N(R8)(R9)-lower alkylene-,N(R8)(R9)-lower
alkylenyloxy-, -S(0)2NH2 and 2-(trimethylsilyl)-ethoxymethyl;
R7 is 1-3 groups independently selected from the group consisting of lower
alkyl, lower alkoxy, -COOH, NO2, -N(R8)(R9), OH, and halogeno;
R& and Rg are independently selected from H or lower alkyl;
R10 is selected from lower alkyl, phenyl, R7-phenyl, benzyl or R7-benzyl;
R11 is selected from OH, lower alkyl, phenyl, benzyl, R7-phenyl or R7-
benzyl;
R12 is selected from H, OH, alkoxy, phenoxy, benzyloxy,
I — v
" N R 13
— . -N(R8)(R9), lower alkyl, phenyl or R7-phenyl;
R13 is selected from -O-, -CH2-. -NH-, -N(lower alkyl)- or -NC(0)Ri9;
R15. R16 and R17 are independently selected from the group consisting of
H and the groups defined for W; or R15 is hydrogen and R16 and R17, together
with adjacent carbon atoms to which they are attached, form a dioxolanyl ring;
Rig is H, lower alkyl, phenyl or phenyl lower alkyl; and
R20 and R21 are independently selected from the group consisting of
phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, indanyl, indenyl,
tetrahydronaphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl,
benzofused heteroaryl, W-substituted benzofused heteroaryl and cyclopropyl,
wherein heteroaryl is as defined above.
6. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (VA) or Formula (VB):
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B
R
A
E-
R4
(VA)
(VB)
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (VA) or (VB) or of the isomers thereof, or prodrugs of the
compounds of Formula (VA) or (VB) or of the isomers, salts or solvates thereof,
wherein:
A is -CH=CH-, -C=C- or -(CH2) P - wherein p is 0, 1 or 2;
D is -(CH2) m C(0)- or -(CH2)q- wherein m is 1 , 2, 3 or 4 and q is 2, 3 or 4;
E is Cio to C20 alkyl or -C(0)-(C9 to C-|g)-alkyi, wherein the alkyl is straight
or branched, saturated or containing one or more double bonds;
R is hydrogen, C1-C15 alkyl, straight or branched, saturated or containing
one or more double bonds, or B-(CH2) r -, wherein r is 0, 1 , 2, or 3;
R1 . R2. R3. R1\ R2'. and R3 1 are independently selected from the group consisting
of hydrogen, lower alkyl, lower alkoxy, carboxy, N0 2 , NH 2 , OH, halogeno, lower
alkylamino, dilower alkylamino. -NHC(0)OR5, R60 2 SNH- and -S(0) 2 NH 2 ;
B is
R
R4 is
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wherein n is 0, 1, 2 or 3;
R5 is lower alkyl; and
R6 is OH, lower alkyl, phenyl, benzyl or substituted phenyl,
wherein the substituents are 1-3 groups independently selected from the group
consisting of lower alkyl, lower alkoxy, carboxy, N0 2 , NH 2 , OH, halogeno, lower
alkylamino and dilower alkylamino.
7. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (VI):
Ar 1 -R 1 -Q
O-G
(VI)
or isomers thereof, or pharmaceutically acceptable salts or solvates of the
compounds of Formula (VI) or of the isomers thereof, or prodrugs of the
compounds of Formula (VI) or of the isomers, salts or solvates thereof, wherein:
R 26 isHor OG 1 ;
G and G 1 are independently selected from the group consisting of
H,
9^JDR 4 OR 4 o^° R7
-^\..„or3 s _/J.„ior3 , -CH 2 -(JVilOR 5
"\o 2 R 2 (}H 2 OR 6 OR 3 0R4
OR 3a
R 4a Q^X*R
0R3 0 0 CH 2 Rt> ;
R 4 0//^Y provided that when R 26 is H or
"^0^*CH 2 R a
OH, G is not H;
R, R a and R D are independently selected from the group consisting of H,
-OH, halogeno, -NH2, azido, (Ci-C6)alkoxy(Ci-C6)-alkoxy and -W-R30;
and
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wherein W is independently selected from the group consisting of -NH-C(O),
-0-0(0}-, -0-C(0)-N(R3l)-, -NH-C(0)-N(R31)- and -0-C(S)-N(R31}-;
R2 and R6 are independently selected from the group consisting of H,
(Ci-C6)alkyl, aryl and aryl(Ci-C6)alkyl;
R 3 , R 4 , R5, r7, R3a and R*a are independently selected from the group
consisting of H, (Ci-C 6 )alkyl, aryKd-CeJalkyl, -C(0)(Ci-C 6 )alkyl and -0(O)aryl;
R 30 is selected from the group consisting of R 32 -substituted T,
R 32 -substituted-T-(Ci-C6)alkyl, R 32 -substituted-(C2-C4)alkenyl,
R 32 -substituted-(Ci -C6)alkyl. R 32 -substituted-(C3-C7)cycloalkyl and
R 32 -substituted-(C3-C7)cycloalkyl(Ci-C6)alkyl;
R 31 is selected from the group consisting of H and (C-|-C4)alkyl;
T is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl,
imidazolyl and pyridyl;
R 32 is independently selected from 1-3 substituents independently selected
from the group consisting of halogeno, (C-|-C4)alkyl, -OH, phenoxy, -CF3, -NO2,
(Ci-C4)alkoxy, methylenedioxy, oxo, (Ci-C4)alkylsulfanyl, (Ci-C4)alkylsulfinyl,
(Ci-C 4 )alkylsulfonyl, -N(CH 3 )2. -C(0)-NH(Ci-C4)alkyl, -C(0)-N((Ci-C4)alkyl)2,
-C(0)-(Ci-C4)alkyl, -C(0)-(Ci-04)alkoxy and pyrrolidinylcarbonyl; or
R 32 is a covalent bond and R31, the nitrogen to which it is attached and R 32
form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group,
or a (Ci-C4)alkoxycarbonyl-substituted pyrrolidinyl. piperidinyl, N-
methylpiperazinyl, indolinyl or morpholinyl group;
Ar1 is aryl or R 1 0-substituted aryl;
Ar 2 is aryl or R 1 1 -substituted aryl;
Q is a bond or. with the 3-position ring carbon of the azetidinone,
^ 1 [-(R 13 ) a
forms the spiro group (R 14 )b — ; and
R 1 is selected from the group consisting of:
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-(CH2)q-, wherein q is 2-6, provided that when Q forms a spiro ring, q
can also be zero or 1 ;
-(CH2)e-E-(CH2)r, wherein E is -0-, -C(O)-, phenylene, -NR 22 - or
-8(0)^2-, e is 0-5 and r \s 0-5, provided that the sum of e and r is 1-6;
-(C2-C6)alkenylene-; and
-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is
0-5, provided that the sum of f and g is 1-6;
Rl2 is
-CH-, -C(C r C 6 alkyl)-, -CF-, -C(OH)-, -C(C 6 H 4 -R 23 )-, -N-, or - + NO" ;
R 13 and R 14 are independently selected from the group consisting of -CH2-,
-CH(d-C6 alkyl)-, -C(di-(Ci-C6) alkyl), -CH=CH- and -C(d-C6 alkyI)=CH-; or
R 12 together with an adjacent R 13 , or R 12 together with an adjacent R 14 , form a
-CH=CH- or a -CH=C(Ci-C6 alkyl)- group;
a and b are independently 0, 1 , 2 or 3, provided both are not zero;
provided that when R 13 is -CH=CH- or -C(Ci-C6 alkyl)=CH-, a is 1;
provided that when R 14 is -CH=CH- or-C(Ci-C6 alkyl)=CH-, b is 1;
provided that when a is 2 or 3, the R1 3, s can be the same or different;
and
provided that when b is 2 or 3, the R 14 's can be the same or different;
and when Q is a bond, R 1 also can be:
R15 R 17 R 15 R15
HVI-Y^C-Z^-.-X^^.-Y-^ or . Xr (C) v -Y r S(O) 0 . 2 -;
R 16 R 18 R16 R«
M is -0-, -S-, -S(O)- or -S(0)2S
X, Y and Z are independently selected from the group consisting of -CH2-,
-CH(C1-C6)alkyl- and -C(di-(Ci-C6)alkyl);
R 10 and R 11 are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of (C<|-C6)alkyl,
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-OR19 -0(C0)R19 -0(CO)OR21, -0(CH 2 )1-50R19, -O(CO)NR19r20,
-NR19R20, -NR19(CO)R20 1 -NR19(C0)0R21, -NR19(CO)NR20r25
-NR19S02R21, -COOR19, -CONR19R20, -COR19, -SO 2 NR19r20 ( S(0)o. 2 r21,
-0(CH2)1-10-COOR19, -O(CK2)1-10CONR19r20 > -(C1-C6 alkyleneJ-COOR^,
-CH=CH-COORl9, .CF3, -CN, -NO2 and halogen;
R 15
and R 17 are independently selected from the group consisting of
-OR1 9, -0(C0)R1 9, -0(CO)OR21 and -0(C0)NR1 9r20 ;
R 16 and R 18 are independently selected from the group consisting of H,
(Ci-C6)alkyl and aryl; or R 15 and R 16 together are =0, or R 17 and R 18 together
are =0;
d is 1 , 2 or 3;
his 0,1,2, 3 or 4;
s is 0 or 1; t is 0 or 1 ; m, n and p are independently 0-4; provided that at
least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when
p is 0 and t is 1 , the sum of m, s and n is 1-5; and provided that when p is 0 and s
is 1 , the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are independently 1-5, provided that the sum of j, k and v is 1-5;
R 15
-X r (C) v -Y k -S(0)o_ 2 -
and when Q is a bond and R 1 is R 16
Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl,
thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R 19 and R20 a re independently selected from the group consisting of H,
(Ci-C6)alkyl, aryl and aryl-substituted (C-|-C6)alkyl;
R21 is (C-|-C6)alkyl, aryl or R24. substituted aryl;
R22 is H, (Ci-C6)alkyl, aryl (C<|-C6)alkyl, -C(0)R 1 9 or-COORl9 ;
R23 and R24 are independently 1-3 groups independently selected from the
group consisting of H, (Ci-C6)alkyl, (C-|-C6)alkoxy, -COOH, NO2, -NR19R20, _OH
and halogeno; and
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R25 is H, -OH or (C-|-C6)alkoxy.
8. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (VII):
or isomers thereof, or pharmaceutically acceptable salts or solvates of the
compounds of Formula (VII) or of the isomers thereof, or prodrugs of the
compounds of Formula (VII) or of the isomers, salts or solvates thereof, wherein:
Ar 1 and Ar2 are independently selected from the group consisting of aryl
and R 4 -substituted aryl;
Ar 3 is aryl or R 5 -substituted aryl;
X, Y and Z are independently selected from the group consisting of -CH2-,
-CH(lower alkyl)- and -C(dilower alkyl)-;
R and R 2 are independently selected from the group consisting of -OR 6 ,
-0(CO)R 6 , -0(CO)OR9 and -0(CO)NR6r7 ;
R 1 and R 3 are independently selected from the group consisting of
hydrogen, lower alkyl and aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently 0, 1 , 2, 3 or 4;
provided that at least one of q and r is 1 , and the sum of m, n, p, q
and r is 1 , 2, 3, 4, 5 or 6; and
provided that when p is 0 and r is 1 , the sum of m, q and n is 1 , 2, 3, 4
or 5;
R 4 is 1-5 substituents independently selected from the group consisting of lower
alkyl, -OR 6 -0(CO)R6 -0(CO)OR9, -©(CI^I-SORe, -0(C0)NR6r7, -NR6r7,
-NR6(CO)R7, -NR6(C0)0R9, -NR6(C0)NR7r8, -NR6SO2R 9 , -COOR 6 ,
R R 2
Ar 1 -X m -(C) q -Y n -(C) r -Z p
R 1 R 3
(VII)
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-CONR6R7, -COR 6 , -S02NR6R7, -S(O)0-2R 9 -0(CH2)1-10-COOR 6 ,
-O(CH2)1.10CONR6r7, -(lower alkyleneJCOOR 6 -CH=CH-COOR 6 , -CF3, -CN,
-NO2 and halogen;
R5 is 1-5 substituents independently selected from the group consisting of -OR 6 ,
-0(CO)R6 -0(CO)OR9 -0(CH2)1.50R 6 , -0(CO)NR6r7, -NR6r7, -NR6(CO)R7 f
-NR6(CO)OR 9 , -NR6(CO)NR7r8, -NR6SO2R 9 -COOR 6 -CONR6r7, -COR 6 ,
-S02NR6R7, -S(O)0-2R 9 , -0(CH2)1-10-COOR6 -0(CH2)1-10CONR 6 R 7 ,
-(lower alkylene)COOR6 and -CH=CH-COOR 6 ;
R6 f R 7 and R 8 are independently selected from the group consisting of
hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and
R 9 is lower alkyl, aryl or aryl-substituted lower alkyl.
9. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (VIII):
or pharmaceutical^ acceptable salts or solvates of the compound of Formula (VIII)
or prodrugs of the compound of Formula (VIII) or of the salts or solvates thereof.
1 0. The method of claim 1 , wherein the at least one sterol absorption
inhibitor is represented by Formula (IX):
(VIII)
OR
(IX)
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91
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (IX) or of the isomers thereof, or prodrugs of the
compounds of Formula (IX) or of the isomers, salts or solvates thereof, wherein:
R26 is selected from the group consisting of:
a) OH;
b) OCH 3 ;
c) fluorine and
d) chlorine.
R 1 is selected from the group consisting of
OR* OR 4 OR^OR 4 0-/ OR7
-(Y.HOR 3 _().„ior 3 . "CH 2 -(~\''IOR 5 .
H ' °~V 2 °"V 6 i~>np4
X0 2 R 2 CH 2 OR OR 3 0R
OR 33
R a % r ^ s s,^ R -S0 3 H; natural and unnatural
or 3 o A 0 ^ CH 2R b • amino acids -
R 4 0/,A^/
CH 2R a
R, R a and R D are independently selected from the group consisting of H,
-OH, halogeno, -NH2, azido, (Ci-C6)alkoxy(C-|-C6)-alkoxy and -W-R 30 ;
W is independently selected from the group consisting of
-NH-C(O)-, -O-C(O)-, -0-C(0)-N(R31)-, -NH-C(0)-N(R31)- and
■ -0-C(S)-N(R31)-;
r2 and R6 are independently selected from the group consisting of H,
(Ci-C6)alkyl, aryl and aryl(Ci-C6)alkyl;
R 3 , r4, R5 t R7 f R3a anc j R4a are independently selected from the group
consisting of H, (Ci-C6)alkyl, aryl(Ci-C6)alkyl, -C(0)(Ci-C6)alkyl and -C(0)aryl;
R 30 is independently selected form the group consisting of
R 3 2-substituted T, R 3 2-substituted-T-(Ci-C6)alkyl,
R 3 2-substituted-(C2-C4)alkenyl, R 32 -substituted-(Ci-C6)alkyl,
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R 32 -substituted-(C3-C7)cycloalkyl and R 32 -substituted-(C3-C7)cycloalkyl(Ci -
C 6 )alkyl;
R 31 is independently selected from the group consisting of H and
(Ci-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyi, iosthiazolyl, benzothiazolyl,
thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R 32 is independently selected from 1-3 substituents independently selected
from the group consisting of H, halogeno, (Ci-C4)alkyl, -OH, phenoxy, -CF3, -NO2,
(Ci-C4)alkoxy, methylenedioxy, oxo, (Ci-C4)alkylsulfanyl. (Ci-C4)alkylsulfinyl,
(Ci-C4)alkylsulfonyl, -N(CH3)2. -C(0)-NH(Ci-C4)alkyl, -C(0)-N((Ci-C4)alkyl)2,
-C(0)-(C1-C4)alkyl, -C(0)-(Cl-C4)alkoxy and pyrrolidinylcarbonyl; or R 32 is a
covalent bond and R 31 , the nitrogen to which it is attached and R 32 form a
pyrrolidinyi, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a
(Ci-C4)alkoxycarbonyl-substituted pyrrolidinyi, piperidinyl, N-methylpiperazinyl,
indolinyl or morpholinyl group;
Ar 1 is aryl or R 10 -substituted aryl;
Ar 2 is aryl or R 1 1 -substituted aryl;
Q is -(CH2)q-, wherein q is 2-6, or, with the 3-position ring carbon of the
azetidinone,
forms the spiro group ;
Rl 2 is
-CH-. -C(C r C 6 alkyl)-, -CF-, -C(OH)-, -C(C 6 H 4 -R 23 )-, -N-. or - + NO" ;
R 13 and R 14 are independently selected from the group consisting of -CH2-,
-CH(Ci-C6 alkyl}-, -C(di-(Ci-C6) alkyl), -CH=CH- and -C(Ci-C6 alkyl)=CH-; or
R 12 together with an adjacent R 13 , or R 12 together with an adjacent R14 ( f orm a
-CH=CH- or a -CH=C(Ci-C6 alkyl)- group;
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a and b are independently 0, 1 , 2 or 3, provided both are not zero; provided
that when R 13 is -CH=CH- or -C(C-|-C6 alkyl)=CH-, a is 1 ; provided that when R 14
is -CH=CH- or -C(Ci-C6 alkyl)=CH- f b is 1; provided that when a is 2 or 3, the
R 1 3's can be the same or different; and provided that when b is 2 or 3, the R 14 's
can be the same or different;
R 10 and R 11 are independently selected from the group consisting of 1-3
substituents independently selected from the group consisting of (C-|-C6)alkyl,
-OR19 -0(CO)R 19 , .0(CO)OR21, -0(CH2)1.50R 19 , -O(CO)NR 1 9r20,
. NR 19 R 20, .nr19(CO)R20, -NR19 ( cO)OR21, -NRl9(CO)NR20R25 f
-NR19S02R 21 . -COOR 19 , -CONR1 9 r20, -COR 19 -SO2NR1 9 r20, S(O)0-2R 21 .
-0(CH2)1.10-COOR19 -O(CH2)1-10CONR19r20 i -(C1-C6 alkylene)-COORl9,
-CH=CH-COOR 19 , -CF3, -CN, -NO2 and halogen;
Ar 1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl,
pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R 19 and R20 are independently selected from the group consisting of H,
(Ci-C6)alkyl, aryl and aryl-substituted (Ci-C6)alkyl;
R21 is (Ci-C6)alkyl, aryl or R 24 -substituted aryl;
R22 js H f (Ci-C6)alkyl, aryl (Ci-C6)alkyl, -C(0)R 19 or-COOR^ 9 ;
R23 and R 24 are independently 1-3 groups independently selected from the
group consisting of H, (Ci-C6)alkyl, (Ci-C6)alkoxy, -COOH, NO2, -NR 19 R 20 , _ 0 H
and halogeno; and
R25 is H f -OH or (Ci-C6)alkoxy.
1 1 . The method of claim 1 0, wherein the at least one sterol absorption
inhibitor is represented by Formula (X):
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X
10
15
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (X) or of the isomers thereof, or prodrugs of the compounds
of Formula (X) or of the isomers, salts or solvates thereof.
12. The method of claim 10, wherein the at least one sterol absorption
inhibitor is represented by Formula (XI):
or isomers thereof, or pharmaceutical^ acceptable salts or solvates of the
compounds of Formula (XI) or of the isomers thereof, or prodrugs of the
compounds of Formula (XI) or of the isomers, salts or solvates thereof.
13. The method according to claim 1 , wherein the sterol absorption
inhibitor is administered to the mammal in an amount ranging from about 0.1 to
about 30 milligrams of sterol absorption inhibitor per kilogram of mammal body
weight per day.
14. The method according to claim 13, wherein the sterol absorption
inhibitor is administered to the mammal in an amount ranging from about 0.1 to
about 15 milligrams of sterol absorption inhibitor per kilogram of mammal body
weight per day.
(XI)
25
1 5. The method of claim 1 , further comprising administering to the
mammal in need of such treatment an effective amount of at least one lipid
lowering agent in combination with the at least one sterol absorption inhibitor.
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16. The method of claim 15, wherein the lipid lowering agent is a HMG-
CoA reductase inhibitor.
17. The method of claim 16, wherein the HMG-CoA reductase inhibitor is
selected from the group consisting of simvastatin, lovastatin, pravastatin,
fluvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.
1 8. The method of claim 1 7, wherein the HMG-CoA reductase inhibitor is
simvastatin or atorvastatin.
19. The method of claim 15, wherein the sterol absorption inhibitor is
administered to the mammal in an amount ranging from about 0.1 to about 30
milligrams of sterol absorption inhibitor per kilogram of mammal body weight per
day.
20. The method of claim 15, wherein the lipid lowering agent is
administered to the mammal in an amount ranging from about 0.1 to about 80
milligrams of lipid lowering agent per kilogram of mammal body weight per day.
21 . The method of claim 1 5, wherein the sterol absorption inhibitor and
lipid lowering agent are present in separate treatment compositions.
22. The method of claim 1 5, comprising:
a)
a sterol absorption inhibitor represented by Formula (VIII):
,OH
F
(VIII)
and
b) at least one HMG-CoA reductase inhibitor.
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23. The method of claim 22, wherein the HMG-CoA reductase inhibitor is
selected from the group consisting of lovastatin, pravastatin, fluvastatin,
simvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.
24. A method of treating or preventing sitosterolemia comprising
administering to a mammal in need of such treatment:
(a) an effective amount of a sterol absorption inhibitor represented by
Formula (VIII):
,OH
(VIII)
and
b) an effective amount of atorvastatin and/or simvastatin.
25. A pharmaceutical composition for the treatment or prevention of
sitosterolemia, comprising an effective amount of the sterol absorption inhibitor
used in the method of Claim 1 in a pharmaceutical^ acceptable carrier.
26. A pharmaceutical composition for the treatment or prevention of
sitosterolemia, comprising an effective amount of the sterol absorption inhibitor
used in the method of Claim 8 in a pharmaceutical^ acceptable carrier.
27. A pharmaceutical composition for the treatment or prevention of
sitosterolemia, comprising an effective amount of the compound of Formula (VIII)
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F
F
(VIII)
in a pharmaceutical^ acceptable carrier.
28. A pharmaceutical composition for the treatment or prevention of
sitosterolemia, comprising:
a) an effective amount of the compound of Formula (VIII)
b) an effective amount of a lipid lowering agent
in a pharmaceutical^ acceptable earner.
29. The composition of claim 28, wherein the lipid lowering agent is a
HMG CoA reductase inhibitor.
30. The composition of claim 29, wherein the HMG CoA reductase
inhibitor is selected from the group consisting of lovastatin, pravastatin, fluvastatin,
simvastatin, atorvastatin, rosuvastatin, itavastatin and mixtures thereof.
(VIII)
and
31 . The composition of claim 30, wherein the HMG CoA reductase
inhibitor is simvastatin or atorvastatin.
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32. A method of treating or preventing sitosterolemia, comprising
administering to a mammal in need of such treatment: (1 ) an effective amount of at
least one sterol absorption inhibitor, or pharmaceutical^ acceptable salt or solvate
of the least one sterol absorption inhibitor, or prodrug of the least one sterol
absorption inhibitor or pharmaceutically acceptable salt or solvate of the least one
sterol absorption, or mixture thereof; and (2) an effective amount of at least one bile
acid sequestrant or other lipid lowering agent.
33. A method of treating or preventing sitosterolemia comprising
administering to a mammal in need of such treatment: (1 ) an effective amount of at
least one sterol absorption inhibitor, or pharmaceutically acceptable salt or solvate
of the least one sterol absorption inhibitor, or prodrug of the least one sterol
absorption or pharmaceutically acceptable salt or solvate of the least one sterol
absorption inhibitor, or mixture thereof; and (2) at least one sterol biosynthesis
inhibitor.
34. A method of reducing plasma or tissue concentration of at least one
non-cholesterol sterol, 5a-stanol, or mixture thereof, comprising administering to a
mammal in need of such treatment an effective amount of at least one treatment
composition comprising an effective amount of at least one sterol absorption
inhibitor or at least one stanol absorption inhibitor, or pharmaceutically acceptable
salt or solvate of the least one sterol absorption inhibitor or the at least one stanol
absorption inhibitor, or prodrug of the least one sterol absorption inhibitor or the at
least one stanol absorption inhibitor or pharmaceutically acceptable salt or solvate
of the least one sterol absorption inhibitor or the at least one stanol absorption
inhibitor, or mixture thereof.
35. The method according to claim 34, wherein the non-cholesterol sterol
is at least one phytosterol.
36. The method according to claim 35, wherein the phytosterol is selected
from the group consisting of sitosterol, campesterol, stigmasterol, avenosterol, and
mixtures thereof.
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37. The method according to claim 36, wherein the phytosterol is selected
from the group consisting of sitosterol and campesteroL
5 38. The method according to claim 34, wherein the 5a-stanol is selected
from the group consisting of cholestanol, 5a-campestanol, 5a-sitostanol and
mixtures thereof.
39. A method of reducing plasma or tissue concentration of at least one
io non-cholesterol sterol, 5a-stanol, or mixture thereof, comprising administering to a
sitosterolemic mammal in need of such treatment an effective amount of at least
one treatment composition comprising an effective amount of at least one sterol
absorption inhibitor or at least one stanol absorption inhibitor, or pharmaceutical^
acceptable salt or solvate of the least one sterol absorption inhibitor or the at least
is one stanol absorption inhibitor, or prodrug of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor or pharmaceutical^
acceptable salt or solvate of the least one sterol absorption inhibitor or the at least
one stanol absorption inhibitor, or mixture thereof.
20 40. The method of 39, wherein the sterol absorption inhibitor is
represented by Formula (VIII)
(VIII) .
25
41 . The method of claim 40, wherein the treatment composition further
comprises at least one lipid lowering agent which is an HMG CoA reductase
inhibitor.
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42. The method of claim 41 , wherein the HMG CoA reductase inhibitor is
simvastatin or atorvastatin.
43. The method of claim 39, further comprising administering to the
mammal in need of such treatment an effective amount of at least one bile acid
sequestrant in combination with at least one of the sterol absorption inhibitors.
44. The method of claim 39, wherein the sterol absorption inhibitor is
represented by Formula (VIII)
,OH
OH 1
(VIII)
and the treatment composition further comprises at least one bile acid sequestrant.
45. The method of claim 44, wherein the bile acid sequestrant is selected
from the group consisting of cholestyramine, colesevelam hydrochloride, and
colestipol.
46. A pharmaceutical composition for the treatment or prevention of
sitosterolemia, comprising:
a) an effective amount of the compound of Formula (VIII)
v
F
(VIII)
and
b) an effective amount of a bile acid sequestrant
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in a pharmaceutical^ acceptable carrier.
47. The composition of claim 46, wherein the bile acid sequestrant is
selected from the group consisting of cholestyramine, colesevelam hydrochloride,
and colestipol.
48. A method of treating vascular disease comprising administering to a
mammal in need of such treatment an effective amount of at least one treatment
composition comprising an effective amount of at least one sterol absorption
inhibitor or at least one stanol absorption inhibitor, or pharmaceutical^ acceptable
salt or solvate of the least one sterol absorption inhibitor or the at least one stanol
absorption inhibitor, or prodrug of the least one sterol absorption inhibitor or the at
least one stanol absorption inhibitor or pharmaceutical^ acceptable salt or solvate
of the least one sterol absorption inhibitor or the at least one stanol absorption
inhibitor, or mixture thereof to reduce plasma or tissue concentration of at least one
non-cholesterol sterol, 5a-stanol or mixture thereof.
49. A method of preventing or reducing arteriosclerosis comprising
administering to a mammal in need of such treatment an effective amount of at
least one treatment composition comprising an effective amount of at least one
sterol absorption inhibitor or at least one stanol absorption inhibitor, or
pharmaceutically acceptable salt or solvate of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor, or prodrug of the least one
sterol absorption inhibitor or the at least one stanol absorption inhibitor or
pharmaceutically acceptable salt or solvate of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor, or mixture thereof to reduce
plasma or tissue concentration of at least one non-cholesterol sterol, 5a-stanol or
mixture thereof.
50. A method of preventing or reducing atherosclerosis comprising
administering to a mammal in need of such treatment an effective amount of at
least one treatment composition comprising an effective amount of at least one
sterol absorption inhibitor or at least one stanol absorption inhibitor, or
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pharmaceutical^ acceptable salt or solvate of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor, or prodrug of the least one
sterol absorption inhibitor or the at least one stanol absorption inhibitor or
pharmaceutical^ acceptable salt or solvate of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor, or mixture thereof to reduce
plasma or tissue concentration of at least one non-cholesterol sterol, 5a-stanol or
mixture thereof.
51 . A method of preventing or reducing risk of a cardiovascular event
comprising administering to a mammal an effective amount of at least one
treatment composition comprising an effective amount of at least one sterol
absorption inhibitor or at least one stanol absorption inhibitor, or pharmaceutical^
acceptable salt or solvate of the least one sterol absorption inhibitor or the at least
one stanol absorption inhibitor, or prodrug of the least one sterol absorption
inhibitor or the at least one stanol absorption inhibitor or pharmaceutical^
acceptable salt or solvate of the least one sterol absorption inhibitor or the at least
one stanol absorption inhibitor, or mixture thereof to reduce plasma or tissue
concentration of at least one non-cholesterol sterol, 5a-stanol or mixture thereof.
52. A method of preventing or reducing risk of a cardiovascular event
comprising administering an effective amount of at least one treatment composition
an effective amount of at least one sterol absorption inhibitor or at least one stanol
absorption inhibitor, or pharmaceutical^ acceptable salt or solvate of the least one
sterol absorption inhibitor or the at least one stanol absorption inhibitor, or prodrug
of the least one sterol absorption inhibitor or the at least one stanol absorption
inhibitor or pharmaceutical^ acceptable salt or solvate of the least one sterol
absorption inhibitor or the at least one stanol absorption inhibitor, or mixture thereof
to reduce plasma or tissue concentration of at least one non-cholesterol sterol, 5a-
stanol or mixture thereof to a mammal having no history of clinically evident
coronary heart disease prior to the initial administration.
53. A method of reducing plasma or tissue concentration of at least one
compound selected from the group consisting of phytosterols, 5a-stanols and
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mixtures thereof, comprising administering to a sitosterolemic mammal in need of
such treatment an effective amount of at least one sterol absorption inhibitor or a
prodrug or a pharmaceutical^ acceptable salt thereof.
54. A method of reducing plasma or tissue concentration of at least one
compound selected from the group consisting of phytosterols, 5a-stanols and
mixtures thereof, comprising administering to a mammal in need of such treatment
an effective amount of at least one sterol absorption inhibitor or a prodrug or a
pharmaceutical^ acceptable salt thereof and at least one lipid lowering agent.
55. A method of reducing plasma or tissue concentration of at least one
compound selected from the group consisting of phytosterols, 5a-stanols and
mixtures thereof, comprising administering to a sitosterolemic mammal in need of
such treatment an effective amount of at least one sterol absorption inhibitor or a
prodrug or a pharmaceutical^ acceptable salt thereof and at least one lipid
lowering agent.
56. A method of reducing plasma or tissue concentration of at least one
compound selected from the group consisting of phytosterols, 5a-stanols and
mixtures thereof, comprising administering to a mammal in need of such treatment
an effective amount of at least one sterol absorption inhibitor or a prodrug or a
pharmaceutical^ acceptable salt thereof and at least one bile acid sequestrant.
57. A therapeutic combination comprising:
a) a first amount of the compound of Formula (VIII)
F
(VIII)
and
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b) a second amount of a lipid lowering agent,
wherein the first amount and the second amount together comprise a
therapeutically effective amount for the treatment or prevention of sitosterolemia in
a mammal.
58. A therapeutic combination comprising:
a) a first amount of the compound of Formula (VIII)
,OH
b) a second amount of a bile acid sequestrant,
wherein the first amount and the second amount together comprise a
therapeutically effective amount for the treatment or prevention of sitosterolemia in
a mammal.
F
(VIII)
and
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